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FORMULATION DESIGN, DEVELOPMENT AND INVITRO EVALUATION OF
IMMEDIATE RELEASE TABLETS OF AMBRISENTAN
BY DIRECT COMPRESSION METHOD.
A Dissertation submitted to
THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY,
CHENNAI- 600 032
In partial fulfilment of the award of the degree of
MASTER OF PHARMACY
IN
Branch-I -- PHARMACEUTICS
Submitted by
Name: THATIPETA S G SREENIVASAN
REG.No. 261610262
Under the Guidance of
Mr. C. KANNAN, M.Pharm.,
ASST PROFESSOR
DEPARTMENT OF PHARMACEUTICS
J.K.K. NATTARAJA COLLEGE OF PHARMACY
KUMARAPALAYAM – 638183
TAMILNADU.
OCT – 2018
FORMULATION DESIGN, DEVELOPMENT AND INVITRO EVALUATION OF
IMMEDIATE RELEASE TABLETS OF AMBRISENTAN
BY DIRECT COMPRESSION METHOD.
A Dissertation submitted to
THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY,
CHENNAI - 600 032
In partial fulfilment of the award of the degree of
MASTER OF PHARMACY
IN
Branch-I -- PHARMACEUTICS
Submitted by
NAME: THATIPETA S G SREENIVASAN
REG.No. 261610262
Under the Guidance of
Mr. C. KANNAN, M.Pharm.,
ASST PROFESSOR
DEPARTMENT OF PHARMACEUTICS
J.K.K. NATTARAJA COLLEGE OF PHARMACY
KUMARAPALAYAM – 638183
TAMILNADU.
OCT – 2018
CERTIFICATES
This is to certify that the dissertation work entitled
“FORMULATION DESIGN, DEVELOPMENT AND INVITRO EVALUATION OF
IMMEDIATE RELEASE TABLETS OF AMBRISENTAN BY DIRECT
COMPRESSION METHOD”, submitted by the student bearing Reg. No:
261610262 to “The Tamil Nadu Dr. M.G.R. Medical University –
Chennai”, in partial fulfilment for the award of Degree of Master of
Pharmacy in Pharmaceutics was evaluated by us during the
examination held on……………..……….
Internal Examiner External Examiner
EVALUATION CERTIFICATE
This is to certify that the work embodied in this dissertation entitled
“FORMULATION DESIGN, DEVELOPMENT AND INVITRO EVALUATION OF
IMMEDIATE RELEASE TABLETS OF AMBRISENTAN BY DIRECT
COMPRESSION METHOD”, submitted to “The Tamil Nadu Dr. M.G.R.
Medical University- Chennai”, in partial fulfilment and requirement of
university rules and regulation for the award of Degree of Master of
Pharmacy in Pharmaceutics, is a bonafide work carried out by the student
bearing Reg.No. 261610262 during the academic year 2017-2018, under the
guidance and supervision of Mr. C. Kannan, M.Pharm., Assistant Professor,
Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy,
Kumarapalayam.
CERTIFICATE
Dr. R. Sambathkumar, M. Pharm., PhD.,
Professor & Principal,
Dr. S. Bhama, M. Pharm., PhD.,
Associate Professor & HOD,
Department of Pharmaceutics
Mr. C. Kannan, M.Pharm.,
Assistant Professor,
Department of Pharmaceutics
This is to certify that the work embodied in this dissertation entitled
“FORMULATION DESIGN, DEVELOPMENT AND INVITRO EVALUATION
OF IMMEDIATE RELEASE TABLETS OF AMBRISENTAN BY DIRECT
COMPRESSION METHOD”, submitted to “The Tamil Nadu Dr. M.G.R.
Medical University - Chennai”, in partial fulfilment and requirement of
university rules and regulation for the award of Degree of Master of
Pharmacy in Pharmaceutics, is a bonafide work carried out by the student
bearing Reg.No. 261610262 during the academic year 2017-2018, under
my guidance and direct supervision in the Department of Pharmaceutics,
J.K.K. Nattraja College of Pharmacy, Kumarapalayam.
Place: Kumarapalayam
Date:
CERTIFICATE
Mr. C. Kannan, M.Pharm.,
Assistant Professor,
Department of Pharmaceutics
This is to certify that the work embodied in this dissertation entitled
“FORMULATION DESIGN, DEVELOPMENT AND INVITRO EVALUATION OF
IMMEDIATE RELEASE TABLETS OF AMBRISENTAN BY DIRECT
COMPRESSION METHOD”, submitted to “The Tamil Nadu Dr. M.G.R.
Medical University- Chennai”, in partial fulfilment and requirement of
university rules and regulation for the award of Degree of Master of
Pharmacy in Pharmaceutics, is a bonafide work carried out by the student
bearing Reg.No. 261610262 during the academic year 2017-2018, under the
guidance and supervision of Mr. C. Kannan, M.Pharm., Assistant Professor,
Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy,
Kumarapalayam.
Place: Kumarapalayam
Date:
CERTIFICATE
Dr. R. Sambathkumar, M. Pharm., PhD.,
Professor & Principal,
J.K.K.Nattraja College of Pharmacy,
Kumarapalayam.
DECLARATON
I do hereby declared that the dissertation “FORMULATION DESIGN,
DEVELOPMENT AND INVITRO EVALUATION OF IMMEDIATE RELEASE
TABLETS OF AMBRISENTAN BY DIRECT COMPRESSION METHOD”
submitted to “The Tamil Nadu Dr. M.G.R Medical University - Chennai”,
for the partial fulfilment of the degree of Master of Pharmacy in
Pharmaceutics, is a bonafide research work has been carried out by me
during the academic year 2017-2018, under the guidance and supervision of
Mr. C. Kannan, M.Pharm., Assistant Professor, Department of
Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Kumarapalayam.
I further declare that this work is original and this dissertation has not
been submitted previously for the award of any other degree, diploma,
associate ship and fellowship or any other similar title. The information
furnished in this dissertation is genuine to the best of my knowledge.
Place: Kumarapalayam Mr. THATIPETA S G SREENIVASAN
Date: Reg.no. 261610262
Dedicated to Parents,
Teachers&
My Family
ACKNOWLEDGEMENT
ACKNOWLEDGEMENT
I am proud to dedicate my deep sense of gratitude to the founder,
(Late) Thiru J.K.K. Nattaraja Chettiar, providing the historical
institution to study.
My sincere thanks and respectful regards to our reverent
Chairperson Smt. N. Sendamaraai, B.Com., and Director
Mr. S. Omm Sharravana, B.Com., LLB., J.K.K. Nattraja Educational
Institutions, Kumarapalayam for their blessings, encouragement and
support at all times.
It is most pleasant duty to thank for our beloved Dr. R.
Sambathkumar, M.Pharm., Ph.D., Principal & Professor, Department of
Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Kumarapalayam for
ensuring all the facilities were made available to me for the smooth
running of this project and tremendous encouragement at each and every
step of this dissertation work. Without his critical advice and deep-rooted
knowledge, this work would not have been a reality.
It is my privilege to express deepest sense of gratitude toward
Mr. C. Kannan, M.Pharm., Assistant Professor, Department of
Pharmaceutics, for their valuable suggestions and inspiration.
Our glorious acknowledgement to our administrative officer
Dr. K. Sengodan, M.B.B.S., for encouraging using kind and generous
manner to complete this work.
My sincere thanks to Dr. S. Bhama, M. Pharm., Ph.D.,
Associate Professor & HOD, Department of Pharmaceutics,
Mr. R. Kanagasabai, B.Pharm, M.Tech., Assistant Professor,
Dr. V. Kamalakannan M. Pharm., Ph.D., Associate Professor, Mr.
K. Jaganathan, M.Pharm., Assistant Professor, Mr. C. Kannan,
M.Pharm., Assistant Professor, Ms. S. Manodhini Elakkiya,
M.Pharm., Lecturer, Mr. M. Subramani, M.Pharm., Lecturer and Dr.
Rosmi Jose, Pharm.D., Lecturer, Department of pharmaceutics for the
in valuable help during my project.
My sincere thanks to Dr. N. Venkateswaramurthy, M.Pharm., Ph.D.,
Professor and Head, Department of Pharmacy Practice,
Dr. P.Balakumar, M.Pharm., Ph.D., Professor, Mrs. K. Krishna Veni,
M.Pharm., Assistant Professor, Mr. R. Kameswaran M.Pharm, Assistant
Professor, Dr. Mebin Alias, Pharm.D., Assistant Professor,
Mrs. P. J. Sujitha, Lecturer, Dr. Cindy Jose, Pharm.D., Lecturer, Dr.
Krishna Ravi, Pharm.D., Lecturer, and Dr. S.K.Sumitha, Pharm.D.,
Lecturer, Department of Pharmacy Practice, for their help during my
project.
It is my privilege to express deepest sense of gratitude toward
Dr. M. Vijayabaskaran, M.Pharm., Ph.D., Professor & Head, Department
of Pharmaceutical chemistry, Dr. S. Satheesh Kumar M.Pharm., Ph.D.,
Assistant professor, Mrs. S. Gomathi M.Pharm., Lecturer,
Mrs. B. Vasuki, M.Pharm., Lecturer, Mr. L. Kaviarasan, Lecturer and
Ms. P. Lekha, Lecturer for their valuable suggestions and inspiration.
My sincere thanks to Dr. V. Sekar, M.Pharm., Ph.D., Professor
and Head, Department of Analysis, Dr. I. Caolin Nimila, M.Pharm.,
Ph.D., Assistant Professor, Mr. D. Kamalakannan Assistant Professor,
Mrs. P. Devi, M.Pharm., Lecturer and Ms. V. Devi, M.Pharm.,
Lecturer, Department of Pharmaceutical Analysis for their valuable
suggestions.
My sincere thanks to Dr. Senthilraja, M.Pharm., Ph.D., Associate
Professor and Head, Department of Pharmacognosy,
Mrs. Meena Prabha, M.Pharm., Lecturer, Department of Pharmacognosy
and Ms. B. Sobha, M.Pharm., Lecturer, Department of Pharmacognosy
for their valuable suggestions during my project work.
My sincere thanks to Dr. R. Shanmugasundaram, M.Pharm.,
Ph.D., Vice Principal & HOD, Department of Pharmacology,
Dr. C. Kalaiyarasi, M.Pharm., Ph.D., Associate
Professor, Mr. V. Venkateswaran, M.Pharm., Assistant Professor,
Mrs. M. Sudha M.Pharm., Lecturer, Mr. T. Thiyagarajan,
M.Pharm., Assistant Professor, Mrs. R. Elavarasi, M.Pharm.,
Lecturer and Mrs. M. Babykala, M.Pharm., Lecturer, Department
of Pharmacology for their valuable suggestions during my project
work.
I greatly acknowledge the help rendered by Mrs. K. Rani, Office
Superintendent, Mr. E. Vasanthakumar, MCA, Assistant
Professor, Miss. M. Venkateswari, M.C.A., typist, Mrs. V.
Vimalaveni, Typist, Mrs. V. Gandhimathi, M.A., M.L.I.S., Librarian,
Mrs. S. Jayakala B.A., B.L.I.S., and Asst. Librarian for their co-
operation. I owe my thanks to all the technical and non-technical staff
members of the institute for their precious assistance and help.
Last, but nevertheless, I am thankful to my lovable parents and
all my friends for their co-operation, encouragement and help
extended to me throughout my project work.
Mr. THATIPETA S G SREENIVASAN
Reg.no. 261610262
CONTENTS
S.NO. CHAPTER PAGE NO
1 INTRODUCTION 1
2 LITERATURE REVIEW 30
3 AIM AND OBJECTIVES 37
4 PLAN OF WORK 39
5 DISEASE PROFILE 40
6 DRUG PROFILE 47
7 EXCIPIENTS PROFILE 51
8 MATERIALS AND EQUIPMENTS 57
9 PREFORMULATION 58
10 FORMULATION 63
11 EVALUATION 64
12 RESULTS AND DISCUSION 72
13 SUMMARY AND CONCLUSION 89
14 BIBILOGRAPHY 90
FORMULATION DESIGN, DEVELOPMENT FORMULATION DESIGN, DEVELOPMENT FORMULATION DESIGN, DEVELOPMENT FORMULATION DESIGN, DEVELOPMENT
AND AND AND AND INVITROINVITROINVITROINVITRO EVALUATION OF IMMEDIATE EVALUATION OF IMMEDIATE EVALUATION OF IMMEDIATE EVALUATION OF IMMEDIATE
RELEASE TABLETS OF AMBRISENTANRELEASE TABLETS OF AMBRISENTANRELEASE TABLETS OF AMBRISENTANRELEASE TABLETS OF AMBRISENTAN
BY DIRECT COMPRESSION METHODBY DIRECT COMPRESSION METHODBY DIRECT COMPRESSION METHODBY DIRECT COMPRESSION METHOD
CHAPTER 1CHAPTER 1CHAPTER 1CHAPTER 1
INTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTION
CHAPTER 2CHAPTER 2CHAPTER 2CHAPTER 2
LITERATURE LITERATURE LITERATURE LITERATURE
REVIEWREVIEWREVIEWREVIEW
CHAPTER 3CHAPTER 3CHAPTER 3CHAPTER 3
AIM AND OBJECTIVEAIM AND OBJECTIVEAIM AND OBJECTIVEAIM AND OBJECTIVE
CHAPTER 4 CHAPTER 4 CHAPTER 4 CHAPTER 4
PLAN OF WORKPLAN OF WORKPLAN OF WORKPLAN OF WORK
CHAPTER 5CHAPTER 5CHAPTER 5CHAPTER 5
DISEASE PROFILEDISEASE PROFILEDISEASE PROFILEDISEASE PROFILE
CHAPTER 6CHAPTER 6CHAPTER 6CHAPTER 6
DRUG PROFILEDRUG PROFILEDRUG PROFILEDRUG PROFILE
CHAPTER 7CHAPTER 7CHAPTER 7CHAPTER 7
EXCIPIENT PROFILEEXCIPIENT PROFILEEXCIPIENT PROFILEEXCIPIENT PROFILE
CHAPTER 8CHAPTER 8CHAPTER 8CHAPTER 8
MATERIALS AND MATERIALS AND MATERIALS AND MATERIALS AND
EQUIPMENTSEQUIPMENTSEQUIPMENTSEQUIPMENTS
CHAPTER 9CHAPTER 9CHAPTER 9CHAPTER 9
PREFORMULATIONPREFORMULATIONPREFORMULATIONPREFORMULATION
CHAPTER 10 CHAPTER 10 CHAPTER 10 CHAPTER 10
FORMULATIONFORMULATIONFORMULATIONFORMULATION
CHAPTER 11CHAPTER 11CHAPTER 11CHAPTER 11
EVALUATION EVALUATION EVALUATION EVALUATION
CHAPTER 12CHAPTER 12CHAPTER 12CHAPTER 12
RESULTS AND RESULTS AND RESULTS AND RESULTS AND
DISCUSSIONDISCUSSIONDISCUSSIONDISCUSSION
CHAPTER 13CHAPTER 13CHAPTER 13CHAPTER 13
SUMMARYSUMMARYSUMMARYSUMMARY AND AND AND AND
CONCLUSIONCONCLUSIONCONCLUSIONCONCLUSION
CHAPER 14CHAPER 14CHAPER 14CHAPER 14
BIBILOGRAPHYBIBILOGRAPHYBIBILOGRAPHYBIBILOGRAPHY
1.INTRODUCTION
Department of Pharmaceutics Page 1
1. INTRODUCTION
Oral route is most popular for systemic effect due to its easy of
ingestion, pain avoidance, versatility and most importantly patient
compliance. Solid oral delivery systems (especially tablets) is system of
choice among all drug delivery system and they do not require special
treatment and are therefore less expensive to manufacture, likewise
immediate release tablets are more acceptable among all the tablets.
Based on their drug-release characteristics, tablets can be classified
into three types, immediate release, extended release and delayed
release. For immediate release tablets the drug is intended to be
released rapidly after administration, or the tablet is dissolved and
administered as a solution. This is the most common type of tablet
and includes disintegrating, chewable, effervescent, sublingual and
buccal tablets. They design to disintegrate and release their
medication with no special rate controlling features. Immediate
Release Tablets are those tablets which are designed to disintegrate
and release their medication with no special rate controlling features,
such as special coatings and other techniques. In pharmaceutical
industries, manufactures of generic tablets are usually focused on the
optimization of the excipients mixture composition to obtain a product
that meet established standard1.
An ideal dosage regimen in the drug therapy of any disease or
the goal of any drug delivery system is the one, which immediately
attains the desired therapeutic concentration of drug in plasma (or at
the site of action) and maintains it constant for the entire duration
treatment.
Pharmaceutical products designed for oral delivery and
currently available on the prescription and over-the-counter markets
are mostly the immediate release type, which are designed for
immediate release of drug for rapid absorption. Immediate release
drug delivery systems are designed to provide immediate drug levels in
short period of time. In recent decades, a variety of pharmaceutical
research has been conducted to develop new dosage forms considering
1.INTRODUCTION
Department of Pharmaceutics Page 2
quality of life, most of these efforts have been focused on ease of
medication.
At present novel drug delivery systems are developed for
expanding markets/indications, extending product life cycles and
generating opportunities. Oral administration is the most popular
route for systemic effects due to its ease of ingestion, pain, avoidance,
versatility and most importantly patient compliance. In these solid
formulations do not require sterile conditions and are therefore,
less expensive to manufacture32.
An immediate release dosage form allows a manufacturer to
extend market exclusivity, while offering patients a convenient dosage
form or dosage regimen. Recently immediate release tablets have
started gaining popularity and acceptance as a drug delivery system,
mainly because they are easy to administer, has quick onset of action
is economical and lead to better patientcompliance. They are also a
tool for expanding markets, extending product life cycles and
generating opportunities. Superdisintegrants are first choice of
excipients which are extensively used for the formulation development
of the immediate release tablets as they effectively result into the
immediate disintegration, release and absorption of the drug after
administration into the body.
1.1 Introduction to Solid Oral Dosage Forms:
Tablet is the most popular among all dosage forms existing
today because of its convenience of self-administration, compactness
and easy manufacturing; Sometimes immediate onset of action is
required than conventional therapy in many cases. Tablets are the
most popular dosage form because of its unique properties such as
ease of administration, low cost and non-invasive therapy
etc.Therapeutic success of any therapy depends on the patient’s
compliance toward the therapy. As a drug entity nears the end of its
patent life, it is common for pharmaceutical manufacturers to develop
a given drug entity in a new and improved dosage form.
1.INTRODUCTION
Department of Pharmaceutics Page 3
A tablet is a pharmaceutical dosage form. It comprises a
mixture of active substances and excipients, usually in powder form,
pressed or compacted from a powder into a solid dose. The excipients
can include diluents, binders or granulating agents, glidants (flow
aids) and lubricants to ensure efficient tableting, disintegrants to
promote tablet break-up in the digestive tract; sweeteners or flavors to
enhance taste, and pigments to make the tablets visually attractive.
Apolymer coating is often applied to make the tablet smoother and
easier to swallow, to control the release rate of the active ingredient, to
make it more resistant to the environment (extending its shelf life), or
to enhance the tablet's appearance.
The compressed tablet is the most popular dosage form in use
today. About two-thirds of all prescriptions are dispensed as solid
dosage forms, and half of these are compressed tablets. A tablet can
be formulated to deliver an accurate dosage to a specific site; it is
usually taken orally, but can be administered sublingually, buccally,
rectally or intra vaginally. The tablet is just one of the many forms
that an oral drug can take such as syrups, elixirs, suspensions, and
emulsions. Medicinal tablets were originally made in the shape of a
disk of whatever color their components determined, but are now
made in many shapes and colors to help distinguish different
medicines. Tablets are often stamped with symbols, letters, and
numbers, which enable them to be identified. Sizes of tablets to be
swallowed range from a few millimeters to about a centimeter.
1.INTRODUCTION
Department of Pharmaceutics Page 4
1.2. Types and Classes of Tablet: 4,5
A. Oral Tablets for Ingestion:
1. Compressed tablets
2. Multiple compressed tablets
3. Layered tablets
4. Compression-coated tablets
5. Repeat-action tablets
6. Delayed-action and enteric-coated tablets
7. Sugar and chocolate-coated tablets
8. Film coated tablets
9. Chewable tablets
B. Tablets Used in the Oral Cavity: 4,5
1. Buccal tablets
2. Sublingual tablets
3. Troches and lozenges
4. Dental cones
C. Tablets Administered by Other Routes: 4,5
1. Implantation tablets
2. Vaginal tablets
D. Tablets Used to Prepare Solutions: 4,5
1. Effervescent tablets
2. Dispensing tablets
3. Hypodermic tablets
4. Tablet triturates
1.INTRODUCTION
Department of Pharmaceutics Page 5
1.3 Introduction to Immediate Release Tablets:6
Definition: Immediate release tablets are those which disintegrate
rapidly and get dissolved to release the medicaments. The term
“release” includes the provision (or presentation) of drug from the
formulation to the gastrointestinal tract, to body tissues and/or into
systemic circulation. In the present case, immediate release may be
provided for by way of an appropriate pharmaceutically acceptable
diluents or carrier, which diluents or carrier does not prolong, to an
appreciable extent, the rate of drug release and/or absorption. It also
finds applications in the field of local delivery of drug to the stomach
and proximal small intestine and importantly in treating
microorganisms (Helicobacter pylori).
In immediate release tablets, disintegration is one of the
important parameter. With the help of design of experiment (DOE)
approach, process variables are first ‘screened’ to determine which are
important to the outcome (excipients type, percentage, disintegration
time (DT), etc. Next step is the ‘optimization’, when the best settings
for the important variables are determined. It involves the use of
‘mixture designs’ for changing mixture composition and exploring how
such changes will affect the properties of the mixture. Immediate
release tablets have gained prominence of being new drug delivery
systems. Most immediate release tablets are intended to disintegrate
in the stomach, where the pH is acidic.
Immediate release drug delivery system are based on single or
multiple-unit reservoir or matrix system, which are designed to
provide immediate drug levels in short period of time.
Immediate release drug delivery is desirable for drugs having
long biological half life, high bioavailability, lower clearance and lower
elimination half life. But main criterion for immediate release dosage
form is poor solubility of the drug and need the immediate action of
drug to treat unwanted defect or disease30.
1.INTRODUCTION
Department of Pharmaceutics Page 6
Immediate release solid oral dosage forms are classified as
either having rapid or slow dissolution rates. Immediate release
dosage forms are those for which ≥85% of labelled amount dissolves
within 30 min. For immediate release tablets, the only barrier to
drug release is simple disintegration or erosion stage, which is
generally accomplished in less than one hour. To enhance dissolution
and hence bioavailability of any drug from immediate release tablets,
disintegration is one of the important process. Few Super-
disintegrants are available commercially as Croscarmellose sodium,
Crospovidone and SSG31.
1.4.DESIRED CRITERIA FOR IMMEDIATE RELEASE DRUG
DELIVERY SYSTEM:
1.4.1. Ideal Properties5
Immediate release dosage form should
1. It should dissolve or disintegrate in the stomach within a short
period In the case of solid dosage.
2. Should show first absorption and dissolution of drug.
3. Rapid onset of action always seen with immediate release tablets.
4. Must be compatible with taste masking.
5. Be portable without fragility concern.
6. It should not leave minimal or no residue in the mouth after oral
administration.
7. Provides pleasing mouth feel.
8. Exhibit low sensitivity to environmental condition as humidity and
temperature.
9. Be manufactured using conventional processing and packaging
equipment at low cost.
1.4.2.Advantages2,3
An immediate release pharmaceutical preparation offers
1. Improved stability, bioavailability.
2. Decreased disintegration and dissolution times for immediate
release oral dosage forms.
1.INTRODUCTION
Department of Pharmaceutics Page 7
3. Suitable for controlled, sustained release actives.
4. High drug loading is possible.
5. Ability to provide advantages of liquid medication in the form of
solid preparation.
6. Adaptable and amenable to existing processing and packaging
machinery.
7. Cost- effective.
8. Improved compliance added convenience.
9. Accurate dose: The immediate/fast dissolve dosage forms have the
added advantages of convenience and accurate dosing as
compared to liquids.
10. Ease of swallowing is possible.
11. Bilayer tablet is possible for sequential release of two drugs in
combination and separate two incompatible substance.
1.4.3.Disadvantage[2][3]
1. Possess swallowing difficulty.
2. Onset of action is slow and depends on disintegration and
dissolution. Some drugs resist compression, due to their
amorphous nature or low-density
3. Drugs having bitter taste, objectionable odor or drugs that are
sensitive to oxygen may require encapsulation or coating of tablet.
4. Drug release at a time may produce high plasma concentration
which may produce toxicity.
5. Frequent dosing is necessary for drug with short half-life.
1.4.4.Salient Features
• Drugs should possessing long biological half-life for immediate
release drug delivery.
• The drug is released quickly and completely in one shot.
• High bioavailability expected with immediate release dosage
form.
• Lower clearance and lower elimination half-life are also
requirement for immediate release drug delivery system.
1.INTRODUCTION
Department of Pharmaceutics Page 8
• But main criterion for immediate release dosage form is poor
solubility of the drug and need the immediate action of drug to
treat unwanted defect or disease.
• Rapid drug therapy intervention is possible.
• New business opportunities like product differentiation, line
extension and lifecycle management, exclusively of product
promotion.
1.5.Criteria for Drug Selection
• Poor solubility of the drug and need immediate drug action in
case of immediate release dosage form.
• The immediate release compositions comprise micronized drug
in an amount sufficient to provide the desired daily dosage, that
is, an amount of about 10 mg to about 1000 mg, more
preferably an amount of about 20 mg to 400 mg.
• Immediate release compositions from which about 50% of the
micronized drug is dissolved in vitro within about 15 minutes,
more preferably at least about 80% of the drug is dissolved in
vitro within about 30 minutes.
• Carrier materials for immediate release compositions preferably
are selected to provide a disintegration time less than about 30
minutes, preferably about 20 minutes or less, more preferably
about 18 minutes or less.
1.6.Unsuitable drug characteristic for immediate release tablets:
• Drug are not suitable for immediate release tablets which
having short biological half-life.
• Drug with low bioavailability are also not desirable candidate for
immediate release tablets.
• Drug with higher clearance and higher elimination half-life
are also not desirable candidate for immediate release
tablets.
1.INTRODUCTION
Department of Pharmaceutics Page 9
1.7.Pharmacokinetics:[6]
In this consideration, study has done on absorption,
distribution, metabolism and excretion. After absorption, drug attains
therapeutic level and therefore elicits pharmacological effect, so
bothrate and extend of absorption is important. In conventional
dosage form there is delay in disintegration and therefore dissolution
is fast. Drug distribution depends on many factors like tissue
permeability, perfusion rate, binding of drug to tissue, disease state,
drug interaction etc. Duration and intensity of action depends upon
rate of drug removal from the body or site of action i.e.
biotransformation. Decrease in liver volume, regional blood flow to
liver reduces thebiotransformation of drug through oxidation,
reduction and hydrolysis. Excretion by renal clearance is slowed, thus
half-life of renal excreted drugs increase.
1.8.Pharmacodynamics:[6]
Drug reception interaction impaired in elderly as well as in
young adult due to undue development of organ.
1. Decreased ability of the body to respond reflexive stimuli,
cardiac output, and orthostatic hypotension may see in taking
antihypertensive like prazosin. Immunity is less and taken into
consideration while administered antibiotics
2. Altered response to drug therapy-elderly show diminished
bronchodilator effect of theophylline shows increased sensitivity
to barbiturates
3. Concomitant illnesses are often present in elderly, which is also
taken into consideration, while multiple drug therapy
prescribed.
1.INTRODUCTION
Department of Pharmaceutics Page 10
1.9.Technology for Immediate release Tablets[6]
Conventional Techniques
Conventional technique used in the preparation of immediate release
tablets
✓ Tablet molding technique
✓ Direct compression technique
✓ Granulation technique
✓ Mass extrusion technique
Several Technologies are available to manufacture immediate release
tablets. The most common preparation methods are molding,
lyophilisation or freeze drying, direct compression, spray drying and
sublimation.
A. Tablet molding technique[4] [6]
Water-soluble ingredients are used in tablet molding technique
which facilitate tablet to disintegrate and dissolve rapidly. A hydro
alcoholic solvent use to moisten powder blend and is molded in to
tablet using compression pressure lower than used in conventional
tablets compression. The solvent is then removed by air-drying. Two
problems commonly encountered are mechanical strength and poor
taste masking characteristics in this technique.
B. Direct compression technique[4] [6]
The term “direct compression” is defined as the process by
which tablets are compressed directly from powder mixture of API and
suitable excipients. No pre-treatment of the powder blend by wet or
dry granulation procedure is required. Amongst the techniques used
to prepare tablets, direct compression is the most advanced
technology. It involves only blending and compression, thus offering
advantage particularly in terms of speedy production, as it requires
fewer unit operations, less machinery, reduced number of personnel
and considerably less processing time along with increased product
stability.
1.INTRODUCTION
Department of Pharmaceutics Page 11
Advantages[6]
1. Direct compression is more efficient and economical process as
compared to other processes, because it involves only dry
blending and compaction of API and necessary excipients.
2. The most important advantage of direct compression is that it is
an economical process. Reduced processing time, reduced labor
costs, fewer manufacturing steps, and less number of
equipment’s is required, less process validation, reduced
consumption of power.
3. Elimination of heat and moisture, thus increasing not only the
stability but also the suitability of the process for thermolabile
and moisture sensitive API.
4. Particle size uniformity.
5. Prime particle dissolution.
In case of directly compressed tablets after disintegration each
primary drug particle is liberated. While in the case of tablets
prepared by compression of granules small drug particles with a
larger surface area adhere together into larger agglomerates, thus
decreasing the surface area available for dissolution.
Disadvantages
a) Excipients Related[6]
1. Problems in the uniform distribution of low dose drugs.
2. High dose drugs having high bulk volume, poor compressibility
and poor flow ability are not suitable for direct compression for
example, Aluminum Hydroxide, Magnesium Hydroxide.
3. The choice of excipients for direct compression is extremely
critical. Direct compression diluents and binders must possess
both good compressibility and good flow ability.
4. Many active ingredients are not compressible either in
crystalline or amorphous forms.
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b) PROCESS Related [7]
1. Capping, lamination, splitting, or layering of tablets is
sometimes related to air entrapment during direct compression.
When air is trapped the resulting tablets expand when the
pressure of tablet is released, resulting in splits or layers in the
tablet.
2. In some case it requires greater sophistication in blending and
compression equipment’s.
C. Granulation technique[4]
Granulation may be defined as a size enlargement process
which converts small particles into physically stronger &larger
agglomerates. The objective of granulation is to improve powder flow
and handling, decrease dustiness, and prevent segregation of the
constituents.
Granulation method can be broadly classified into two types
(i) Wet granulation[4]
(ii) Dry granulation[4]
Ideal characteristics of granules
The ideal characteristics of granules include spherical shape,
smaller particle size distribution with sufficient fines to fill void spaces
between granules, adequate moisture (between 1-2%), good flow, good
compressibility and sufficient hardness etc.
The effectiveness of granulation depends on the following
properties:
• Particle size of the drug and excipients
• Type of binder (strong or weak)
• Volume of binder (less or more)
• Wet massing time (less or more)
• Amount of shear applied
• Drying rate (Hydrate formation and polymorphism)
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(i) Wet granulation[4]
Wet granulation is a commonly used unit operation in the
pharmaceutical industry. Wet granulation is often carried out utilizing
a high-shear mixer. The high-shear granulation process is a rapid
process which is susceptible for over-wetting. Thus, the liquid amount
added is critical and the optimal amount is affected by the properties
of the raw materials. Power consumption of the impeller motor and
the impeller torque have been applied to monitor the rheological
properties of the wet mass during agglomeration and, thereby, have
been used to determine the end-point of water addition. However,
these methods are affected by the equipment variables.
Important steps involved in wet granulation
• Mixing of drug(s) and excipients.
• Preparation of binder solution.
• Mixing of binder solution with powder mixture to form wet
mass.
• Course screening of wet mass using a suitable sieve (6-12
screens).
• Drying of moist granules.
• Screening of dry granules through a suitable sieve (14-20
screen).
• Mixing of screened granules with disintegrant, glidant, and
lubricant.(Manish
Limitation of wet granulation[4]
• The greatest disadvantage of wet granulation is its cost. It is an
expensive process because of labor, time, equipment, energy
and space requirements.
• Loss of material during various stages of processing.
• Stability may be a major concern for moisture sensitive or
thermolabile drugs.
• An inherent limitation of wet granulation is that any
incompatibility between formulation components is aggravated.
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1.10.Special wet granulation techniques
▪ High shear mixture granulation
▪ Fluid bed granulation
▪ Extrusion-spheronization
▪ Spray drying
(ii) Dry granulation[4]
In dry granulation process the powder mixture is compressed
without the use of heat and solvent. The two basic procedures are to
form a compact of material by compression and then to mill the
compact to obtain granules.
Two methods are used for dry granulation.The more widely used
method is slugging, where the powder is precompressed and the
resulting tablets or slugs are milled to yield granules.The other
method is to precompress the powder with pressure rolls using a
machine such as Chilosonator.
Advantages
The main advantages of dry granulation or slugging are that it
uses less equipment’s and space. It eliminates the need for binder
solution, heavy mixing equipment and the costly and time consuming
drying step required for wet granulation.
Slugging can be used for advantages in the following situations
▪ For moisture sensitive material
▪ For heat sensitive material
▪ For improved disintegration since powder particles are not
bonded together by a binder.
Disadvantages
• It requires a specialized heavy duty tablet press to form slug.
• It does not permit uniform color distribution as can be achieved
with wet granulation where the dye can be incorporated into
binder liquid.
• The process tends to create more dust than wet granulation,
increasing the potential contamination.
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Steps in dry granulation
1. Milling of drugs and excipients
2. Mixing of milled powders
3. Compression into large, hard tablets to make slug
4. Screening of slugs
5. Mixing with lubricant and disintegrating agent
6. Tablet compression
Two main dry granulation processes
a) Slugging process
Granulation by slugging is the process of compressing dry
powder of tablet formulation with tablet press having die cavity large
enough in diameter to fill quickly. The accuracy or condition of slug is
not too important. Only sufficient pressure to compact the powder
into uniform slugs should be used. Once slugs are produced they are
reduced to appropriate granule size for final compression by screening
and milling.
b) Roller compaction
The compaction of powder by means of pressure roll can also be
accomplished by a machine called Chilosonator. Unlike tablet
machine, the Chilosonator turns out a compacted mass in a steady
continuous flow. The powder is fed down between the rollers from the
hopper to feed the powder into the compaction zone. Like slugs, the
aggregates are screened or milled for production into granules.
D. Mass-Extrusion technique
Here softening of active blend done with solvent mixture of
water-soluble polyethylene glycol and methanol and subsequent
expulsion of softened mass through the extruder or syringe to get a
cylinder of the product into even segments using heated blade to form
tablets. In case of bitter drug granules can be coated with the help of
dried cylinder to achieve taste masking.
Solid dispersions method:
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The immediate release dosage forms containing a solid
dispersion that enhances the Solubility of a “low-solubility drug,”
meaning that the drug may be either “substantially Water-insoluble,”
which means that the drug has a minimum aqueous solubility at
physiologically relevant pH (e.g., pH 1-8) of less than 0.01 mg/mL,
“sparingly water-soluble,” that is, has an aqueous solubility up to
about 1to2 mg/mL, or even low to moderate aqueous- solubility,
having an aqueous-solubility from about 1 mg/mL to as high as about
20 to 40 mg/ml.
1.11.Few therapeutical area uses in the formulation of immediate
release dosage form33:
1. Analgesics and Anti-inflammatory Agents: Ibuprofen,
Indomethacin, Ketoprofen, Meclofenamic Acid, Mefenamicacid,
Nabumetone, Oxyphenbutazone.
2. Anthelmintics: Albendazole, Mebendazole, Oxantel, Embonate,
Embonate, Thiabendazole.
3. Anti-Arrhythmic Agents: Amiodarone Hcl, Disopyramide.
4. Anti-bacterial Agents: Penicillin, Ciprofloxacin HCl,
Clarithromycin, Clofazimine, Doxycycline, Erythromycin, Nalidixic
Acid, Nitrofurantoin, Rifampicin, Sulphabenzamide,
Sulphamethoxazole, Sulphapyridine, Trimethoprim.
5. Anti-coagulants: Dicoumarol, Dipyridamole.
6. Anti-depressants: Amoxapine, Ciclazindol, Maprotiline HCl,
Mianserin HCl,Trazodone HCl.
7. Histamine H,-Receptor Antagonists: cyclizine, cyproheptadine
HCl, dimenhydrinate, flunarizine HCl.
8. Anti-diabetics: Acetohexamide, Chlorpropamide, Glibenclamide,
Gliclazide, Glipizide.
9. Anti-hypertensive Agents: Amlodipine, Carvedilol, Benidipine,
Darodipine, Dilitazem HCl, Diazoxide, Guanabenz Acetate,
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Indoramin, Isradipine, Minoxidil, Nicardipine HCl, Nifedipine,
Nimodipine, Reserpine.
10. Gastro-intestinal Agents: cimetidine, cisapride, diphenoxylate
HCl,famotidine, loperamide, mesalazine, nizatidine, omeprazole.
11. Diuretics: Acetazolamide, amiloride, bendrofluazide, bumetanide,
chlorothiazide, chlorthalidone, ethacrynic acid, frusemide,
metolazone, spironolactone, triamterene.
12. Cardiac Inotropic Agents: Amrinone, Digitoxin, Digoxin,
Enoximone, Lanatoside C, Medigoxin.
13. Anxiolytic, Sedatives, Hypnotics and Neuroleptics: Etizolam,
Alprazolam, Amylobarbitone, Barbitone, Bentazepam,
Bromazepam, Bromperidol, Brotizolam, Chlormethiazole,
Chlorpromazine, Diazepam, Droperidol.
14. Histamine H,-Receptor Antagonists: Acrivastine, astemizole,
cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate,
flunarizine HCl.
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1.12.DISINTEGRANTS:
Disintegrants are agents added to tablet and some
encapsulated formulations to promote the breakup of the tablet and
capsule “slugs’ into smaller fragments in an aqueous environment
there by increasing the available surface area and promoting a more
rapid release of the drug substance. Superdisintegrants are generally
used at a low level in the solid dosage form, typically 1- 10 % by
weight relative to the total weight of the dosage unit. Diverse
categories of Superdisintegrants such as synthetic, semi-synthetic,
natural and co-processed blends etc. have been employed to develop
effective immediate release tablets and to overcome the limitations of
conventional tablet dosage form.36
They promote moisture penetration and dispersion of the
tablet matrix. Tablet disintegration has received considerable
attention as an essential step in obtaining fast drug release. The
disintegrants have the major function to oppose the efficiency of the
tablet binder and the physical forces that act under compression to
form the tablet. The stronger the binder, the more effective must be
the disintegrating agents in order for the tablet to release its
medication. Ideally, it should cause the tablet to disrupt, not only into
the granules from which it was compressed, but also into powder
particles from which the granulation was prepared. Most common
tablets are those intended to be swallowed whole and to
disintegrate and release their medicaments rapidly in the
gastrointestinal tract (GIT). The proper choice of disintegrant and its
consistency of performance are of critical importance to the
formulation development of such tablets. In more recent years,
increasing attention has been paid to formulating not only fast
dissolving and/or disintegrating tablets that are swallowed, but
also orally disintegrating tablets that are intended to dissolve
and/or disintegrate rapidly in the mouth. Most prior studies have
focused on the function related properties of superdisintegrants with
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special emphasis on correlating these functional properties to
disintegrant efficiency and drug release rate.37
1.13.MECHANISM OF DISINTEGRATION BY
SUPERDISINTEGRANTS:
There are five major mechanisms for tablet disintegration as follows:-
1) Swelling
2) Porosity and Capillary Action (Wicking)
3) Deformation
4) Due to disintegrating particle/particle repulsive forces
5) Enzymatic reaction
1. Swelling:
Swelling is believed to be a mechanism in which certain
disintegrating agents (such as starch) impart the disintegrating
effect. By swelling in contact with water, the adhesiveness of
other ingredients in a tablet is overcome causing the tablet to
fall apart. E.g Sodium starch Glycolate.38
Fig.1. Swelling of granules due to superdisintegrants
2. Porosity and Capillary Action (Wicking):
Effective disintegrants that do not swell are believed to
impart their disintegrating action through porosity and capillary
action. Tablet porosity provides pathways for the penetration of
fluid into tablets. The disintegrant particles (with low
cohesiveness & compressibility) themselves act to enhance
porosity and provide these pathways into the tablet. Liquid is
drawn up or “wicked” into these pathways through capillary
action and rupture the interparticulate bonds causing the tablet
to break apart. E.g. Crospovidone, Crosscarmillose.39
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Fig.2. Wicking & Swelling
3. Deformation:
Starch grains are generally thought to be “elastic” in
nature meaning that grains that are deformed under
pressure will return to their original shape when that pressure
is removed. But, with the compression forces involved in
tableting, these grains are believed to be deformed more
permanently and are said to be “energy rich” with this energy
being released upon exposure to water. In other words, the
ability for starch to swell is higher in “energy rich” starch grains
than it is for starch grains that have not been deformed under
pressure.40
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Fig.3. Deformation and repulsion
4. Due to disintegrating particle/particle repulsive forces:
Another mechanism of disintegration attempts to explain
the swelling of tablet made with “nonswellable” disintegrants.
Guyot-Hermann has proposed a particle repulsion theory
based on the observation that nonswelling particle also cause
disintegration of tablets. The electric repulsive forces between
particles are the mechanism of disintegration and water is
required for it. Researchers found that repulsion is secondary to
wicking. It is believed that no single mechanism is responsible
for the action of most disintegrants. But rather, it is more likely
the result of inter-relationships between these major
mechanisms.
5. By Enzymatic Reaction:
Enzymes present in the body also act as disintegrants.
These enzymes enhance the binding action of binder and
helps in disintegration. Due to swelling, pressure is exerted in
the outer direction that causes the tablet to burst or the
accelerated absorption of water leads to an enormous increase
in the volume of granules to promote disintegration.41
When it comes to immediate-release tablet formulations,
the choice of disintegrant can have a significant effect on the
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rate and extent of drug dissolution. Once a tablet disintegrates,
the characteristics of the API, either alone or assisted by other
formulation ingredients, determine the dissolution rate and
extent of the API. Thus, the choice of superdisintegrant is
important, especially with poorly soluble APIs.
Fig.4. Enzymes enhance helps in disintegration
1.14.NOT ALL SUPERDISINTEGRANTS ARE THE SAME:
The three most common classes of superdisintegrants are:
crospovidone, croscarmellose sodium and sodium starch glycolate. In
general, all of these provide rapid disintegration at low use levels in
both wet and dry granulations and direct compression tablet
processes; however, the classes of disintegrants differ in chemistry
and particle morphology. Crospovidone possesses unique pyrrolidone
chemistry and a highly porous particle morphology that results in
high surface area. The high surface area combined with unique
chemistry results in high-interfacial activity that serves to enhance
the dissolution of poorly soluble drugs in a way that is not
possible with other disintegrant technologies. Indeed, studies have
shown that tablets containing a poorly soluble API and crospovidone,
Type B, have significantly faster dissolution rates compared with
tablets formulated with other superdisintegrants.
It has been widely reported that more than 60% of drugs in
development and over 40% of recently launched drugs have issues
related to poor solubility, leading to long development times or
cancellations. Before evaluating advanced techniques, such as
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amorphous solid dispersions, more traditional approaches such as the
influence of superdisintegrants on dissolution are now being
considered. The selection of a superdisintegrant and the use level
plays a key role in determining the drug release of finished
formulations.
1.15.CHOOSING AN OPTIMAL SUPERDISINTEGRANT:
It is important to consider the impact of the superdisintegrant with
respect to the performance of the final dosage form. As drug
dissolution is essential for absorption by the body, formulators no
longer select disintegrants based on the lowest disintegration time
because it is important to also consider the effect of the
superdsintegrant on dissolution. Additionally, the ionic nature of both
the API and the superdisintegrants must also be considered. Anionic
superdisintegrants, such as croscarmellose sodium and sodium
starch glycolate, can interact with cationic APIs and retard
dissolution. Thus, nonionic superdistegrants are preferred when
working with cationic APIs. Formulators also consider the impact of
the superdisintegrant on physical tablet characteristics, such as tablet
breaking force and friability. In today’s high-speed tablet presses,
superdisintegrants that provide tablets with high breaking force and
low friability, while maintaining fast disintegration, are particularly
important.42
1.16.SELECTION OF SUPERDISINTEGRANT:
Since superdisintegrant is used as an excipient in the tablet
formulation, it has to meet certain criteria other than its swelling
properties. The requirement placed on the tablet disintegrant should
be clearly defined. The ideal disintegrants should have 43
1. Poor solubility
2. Poor gel formation
3. Good hydration capacity
4. Good moulding and flow properties
5. No tendency to form complexes with the drugs
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Department of Pharmaceutics Page 24
6. Good mouth feel.
7. It should also be compatible with the other excipients and
have desirable tableting properties.
Three major groups of compounds have been developed
which swell to many times their original size when placed in water
while producing minimal viscosity effects. Different commonly used
superdisintagrants are:44
1. Modified Starches - Sodium Carboxymethyl Starch
(Chemically treated Potato Starch) i.e. Sodium Starch
Glycolate (Explotab, Primogel).
Mechanism of Action: Rapid and extensive swelling with
minimal gelling.
Effective Concentration: 4-6%. Above 8%, disintegration
times may actually increase due to gelling and its subsequent
viscosity producing effects.
2. Cross-linked polyvinylpyrrolidone - water insoluble and
strongly hydrophilic. i.e. crospovidone (Polyplasdone XL,
Kollidon CL).
Mechanism of Action: Water wicking, swelling and possibly
some deformation recovery.
Effective Concentration: 2-4%
3. Modified Cellulose - Internally cross-linked form of Sodium
carboxymethyl cellulose. i.e. Ac-Di-Sol (Accelerates
Dissolution), Nymcel
Mechanism of Action: Wicking due to fibrous structure, swelling
with minimal gelling.
Effective Concentrations: 1-3% (Direct Compression), 2-4% (Wet
Granulation)
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1.17.METHOD OF ADDITION OF SUPERDISINTEGRANTS:
There are three methods of incorporating disintegrating agents
into the tablet.
i) Internal Addition
In wet granulation method, the disintegrant is added to other
excipients before wetting the powder with the granulating fluid.
Thereby, the disintegrant is incorporated within the granules. In dry
granulation method, the disintegrant is added to other excipients
before compressing the powder between the rollers. In a computer
optimized experiment, the study show the effect of incorporating a
disintegrant, croscarmellose sodium, intragranularly, extra granularly
or distributed equally between the two phases of a tablet in which a
poorly soluble drug constituted at least 92.5% of the formulation. The
results analyzed by means of a general quadratic response surface
model suggest that, tablets with the same total concentration of
crosscarmellose sodium dissolve at a faster rate when the super
disintegrant is included intragranularly. Tablet friability is not affected
by the method of disintegrant incorporation.
ii) External Addition
In both wet and dry granulation method, the superdisintegrant
is added to the granules during dry mixing prior to compression. The
effect of mode of incorporation of superdisintegrants (croscarmellose
sodium, sodium starch glycolate and crospovidone) on dissolution of
three model drugs with varying aqueous solubility (carbamazepine,
acetaminophen and cetrizine HCl) from their respective tablet
formulations by wet granulation was studied. It is proved that
crospovidone is effective in improving the dissolution of the drugs in
extra granular mode of addition seems to be the best mode of
incorporation, irrespective of the solubility of the main tablet component.
iii) Internal and External Addition
In this method, disintegrant is divided into two portions. One
portion is added before granule formation (intra) and
remaining portion is added to granules (extra) with mixing prior to
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compression. This method can be more effective. If both intragranular
and extragranular methods are used, extra- granular portion break
the tablet into granules and the granules further disintegrate by
intra-granular portion to release the drug substance into solution.
However, the portion of intra-granular disintegrant (in wet granulation
processes) is usually not as effective as that of extra-granular due to
the fact that it is exposed to wetting and drying (as part of the
granulation process) which reduces the activity of the disintegrant.
Since a compaction process does not involve its exposure to wetting
and drying, the intragranular disintegrant tends to retain good
disintegration activity.44
Table-1 List of Common Disintegrants and Superdisintegrants
Name of excipients
Category Concentration Stability criteria
Alginic acid Disintegrants 1-5% Hydrolyzes slowly at room temperature
ColloidalSilicon Dioxide
Disintegrants 5-10% Hydroscopic , but do not liquefy upon absorption of water
Cross- povidone Superdisintegrants 2-5 %
As hygroscopic in nature, stored in an air- tight container, in a cool and dry place.
Methyl cellulose Disintegrants 2-10% Slightly hygroscopic, but stable
Micro-crystalline cellulose
Superdisintegrants 5-15% Stable at dry and air tight condition
Starch Superdisintegrants 5-10% Stable at dry and air tight condition
1.18.ADVANTAGES OF SUPERDISINTEGRANTS:
The uses of superdisintegrants are extended in the applications
of immediate release tablets, oral disintegration tablets, fast-
dispersible tablets, capsules, mouth-dissolving films, etc
• Remarkable tendency on wetting causing rapid
disintegration
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Department of Pharmaceutics Page 27
• No lump formation on disintegration
• Compatible with commonly used therapeutical agents and
excipients
• Work equally effective in hydrophilic and hydrophobic
formulations.
• Provides good mechanical strength to the tablet facilitating
easy packing and transportation.
• Does not stick to the punches and dyes.
• Although there are many superdisintegrants, which show superior
disintegration, the search for newer disintegrants is ongoing and
researchers are experimenting with modified natural products.45
1.19.EVALUATION OF TABLETS:
These tests are as following:-
1. Appearance
2. Thickness
3. Hardness
4. Weight variation
5. Friability
6. Disintegration
7. Uniformity of dispersion
8. Wetting Time
9. Water absorption ratio
10. Drug content
11. In vitro Dissolution
12. Stability studies
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1.20.CHALLENGES AND LIMITATIONS FOR ODTS:
Drugs with relatively larger doses, are difficult to formulate into
ODTs e.g. antibiotics like ciprofloxacin with adult dose tablet
containing about 500 mg of the drug.
The application for technologies used for ODTs is limited by the
amount of drug into each unit dose. The drug dose must be lower
than 400mg for insoluble drugs and 60mg for soluble drugs.
However Flashdose technology can accommodate larger drug
doses and offers improved mechanical strength. Orasolv® technology
can accommodate a wide range of active pharmaceutical ingredient
from 1 mg to 500 mg.
Mechanical strength - ODTs are made of porous or soft molded
matrices in order to allow its disintegration in mouth. This makes
tablet friable and handling becomes difficult.
Orodispersible tablets with highly porous structure and good
mechanical strength have been developed by sublimation method.
Also Durasolv® has much higher mechanical strength than Orasolv
due to the use of higher compaction pressures during compression.
Palatability - ODTs are intended to be dissolved in mouth. Most of the
drugs have bitter taste. Bitter taste can be masked with
enough sweetener and flavors. Specifically, methods of taste masking
include lipophilic vehicles, coating with polymers, carbohydrates,
lipids or proteins complexation with cyclodextrins or ion-exchange
resins, formation of salts, use of salting out layers and solid
dispersions. OraQuick utilizes its own patented taste masking
technology i.e. MicroMask®. In MicroMask® technology, taste-
masking process is done by incorporating drug into matrix
microsphere.
Drugs in form of ODTs are hygroscopic in nature and hence need to
be protected from humidity. To overcome humidity problem special
working facilities can be designed by simple methods and special air-
conditioning systems can be set up. Size of tablet 7 and 8 mm are
easy to swallow while tablets of size 8mm are easy to handle. Hence,
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Department of Pharmaceutics Page 29
tablet sizes which are both easy to handle and swallow are difficult to
achieve. For the patient compliance, to make the swallowing easier,
round shape punches having optimum dimensions can be used.
Drug candidates should be stable both in water and in saliva,
should not ionize at oral cavity pH and should be able to permeate
oral mucosal tissue to diffuse and partition in upper GI epithelium
(logP > 1, or preferably > 2, not have short half-life). To optimize
solubility problem of the active pharmaceutical ingredient some solid
buffers and surfactants can also be chosen.
ODT requires special packaging for proper stabilization and safety of
stable product.
1.21.Future of ODTs:
ODT technology is applicable to a wide range of therapeutic
agents including generics, thereby adding value, i.e. "supergenerics"
for veterinary or human application.
Some new quality control methods can be developed to determine the
technological aspects of orally disintegrating tablets to define the
characteristics of ODTs.
Protein and peptide–based therapeutics that used via oral route,
have limited bioavailability when administered by immediate release
tablets. Those kinds of products usually degrade immediately in
gastrointestinal system. The developments of improved oral protein
delivery Technology by ODTs, that dispersed and/or dissolved in the
saliva, are very promising for the delivery of high molecular weight
protein and peptide.
It would be an innovative improvement in the ODT technology
when development of ODTs with controlled release properties that can
deliver drugs which has short half-lives like 12–24 hours. The added
convenience and compliance of such formulations will be used more
immensely.
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2. LITERATURE REVIEW
Nivedithaa V.R. et al., [2018] has studied on the obesity is known to
have significant impact on physical and psychological health related
issues in many countries. Combination therapy of Atorvastatin Calcium,
a lipid lowering agent and Bisoprolol Fumarate, an antihypertensive
agent was preferred for obesity treatment. The present research work
was envisaged to develop immediate release tablet of Atorvastatin
Calcium and Bisoprolol Fumarate by direct compression method to
minimize dose dependent side effect and improve patient compliance for
obese people. The formulation that showed more than 90% release was
considered to be optimized formulation of combination tablet. Study
reveals that combination of beta-blocker and statins were good candidate
for blood pressure and lowering lipoproteins in obese patient and may
increases patient compliance by reducing the multi dosage form therapy
and prescription costs.34
Safila Naveed et al., [2016] has discussed about the stability of the
pharmaceutical formulation during its entire shelf life in its final
packaging as an important matter. Stability study does not only cover
the physiochemical aspects of the drug but also explains the safety and
efficacy of the product during its entire shelf life. Force degradation
studies are the studies in which stress conditions or accelerated
conditions are provided to the drug in bulk or product. For the
development of stability indicating methods especially when insufficient
information is accessible about degradation products and to obtain
information about the degradation pathways and degradations products
that might affect during storage conditions forced degradation studies
are performed. Forced degradation studies help to facilitate
pharmaceutical development, manufacturing, production and packaging
where knowledge of chemical behavior can be used to improve drug
2.LITERATURE REVIEW
Department of Pharmaceutics Page 31
product. An FDA and ICH regulatory body portrays the layout of these
stability limitations for the stability and degradation point of view.
Priyanka Patel et al., [2015] has discussed that the Studies of drug-
excipient compatibility represent an important phase in the
preformulation stage for the development of all dosage forms. The
potential physical and chemical interactions between drugs and
excipients can affect the chemical, physical, therapeutical properties and
stability of the dosage form. The present review contains a basic mode of
drug degradation, mechanism of drug- excipient interaction like
physical, chemical and biopharmaceutical. Different Thermal and Non-
thermal method of analysis, Tools and software for incompatibility is also
discussed. Once the type of interaction is determined we can take further
steps to improve the stability of drug and dosage form. From review, we
conclude that consequent use of thermal and non-thermal method
provide data for drug- excipient interaction which can further help in
selection of excipient for the development of stable dosage form.
Ramdooss Karthikeyan et al., (2015) described the method of analysis
for ambrisentan in pharmaceutical dosage form by reverse phase HPLC
using C-18 coloumn(4.6 X 250mm) and 10mM phosphate buffer(pH 6.0),
acetonitrile(50:50, v/v) is used as mobile phase and eluents were
monitored at 226nm. The method has shown a good linearity in
concentration range 6-30 mg/ml.
Honey Kanasara et al., (2015) described the novel technique that can
enhance the solubility of BCS class II drug. The technique includes use
of cosolvents, Hydrotropy, Micronization, change in dielectric constant of
solvent, amorphous forms, chemical modification of drug, use of
surfactants, inclusion complex, alteration of pH of solvent, use of
hydrates or solvates, use of soluble prodrugs, application of ultrasonic
waves, functional polymer technology, controlled precipitation
2.LITERATURE REVIEW
Department of Pharmaceutics Page 32
technology, evaporative precipitation in aqueous solution, use of
precipitation inhibitors, solvent deposition, precipitation, selective
adsorption on insoluble carriers. Novel drug delivery technologies
developed in recent years for solubility enhancement of insoluble drugs
are size reduction technologies, lipid based delivery system, micellar
technologies, porous micro particle technology. Solid Dispersion
Technique and various types of solid dispersion systems have also been
explained briefly.
Jishan Ali Ahmed et al., (2015) expressed various advantages
including ease of ingestion, avoidance of pain, versatility and most
importantly patient compliance. Sometimes immediate onset of action is
considered obligatory immediate release tablets are the final option.
Recently immediate release tablets have started gaining popularity and
acceptance as a drug delivery system, mainly because they are easy to
administer and lead to better patient compliance. In the present work, we
engage in discussion about formulation, development and evaluation of
immediate release tablets. They are also a tool for expanding markets,
extending product life cycles and generating opportunities.
Virender Kaur et al., (2015) studied about the disntegrants in
Immediate drug release dosage forms disintegrate rapidly after
administration with enhanced rate of dissolution. The basic approach
used in development tablets is the use of superdisintegrants like Cross
linked Polyvinylpyrrolidone or crospovidone (Polyplasdone), Sodium
starch glycolate (Primogel, Explotab), carboxymethylcellulose
(Croscarmellose) etc. These superdisintegrants provide instantaneous
disintegration of tablet after administration in stomach.35
Bhandari Neeraj et al., [2014] has discussed that tablet is the most
popular among all dosage forms existing today because of its
convenience of self administration,compactness and easy manufacturing;
2.LITERATURE REVIEW
Department of Pharmaceutics Page 33
however in many cases immediate onset of action is required than
conventional therapy. To overcome these drawbacks, immediate release
pharmaceutical dosage form has emerged as alternative oral dosage
forms. There are novel types of dosage forms that act very quickly after
adminstration. The basic approach used in development tablets is the
use of superdisintegrants like Cross linked carboxymelhylcellulose
(Croscarmellose), Sodium starch glycolate (Primogel, Explotab),
Polyvinylpyrrolidone (Polyplasdone) etc. which provide instantaneous
disintegration of tablet after administration. The development of
immediate release tablets also provides an opportunity for a line
extension in the market place. A wide range of drugs (e.g., cardiovascular
drugs, analgesics, antihistamines, and drugs can be considered
candidates for this dosage form. As a drug entity nears the end of its
patent life, it is common for pharmaceutical manufacturers to develop a
given drug entity in a new and improved dosage form. Immediate release
dosage form allows a manufacturer to extend market exclusivity, while
offering its patient population a more convenient dosage form or dosing
regimen. Now a day, immediate release formulations are similar to many
sustained release formulations that are now commonly available.[9]
Shweta Gupta et al., [2013] has discussed that Poorly water-soluble
drug candidates are becoming more prevalent. It has been estimated that
approximately 60–70% of the drug molecules are insufficiently soluble in
aqueous media and/or have very low permeability to allow for their
adequate and reproducible absorption from the gastrointestinal tract
(GIT) following oral administration. Formulation scientists have to adopt
various strategies to enhance their absorption. Lipidic formulations are
found to be a promising approach to combat the challenges. In this
review article, potential advantages and drawbacks of various
conventional techniques and the newer approaches specifically the self-
emulsifying systems are discussed. Various components of the self-
2.LITERATURE REVIEW
Department of Pharmaceutics Page 34
emulsifying systems and their selection criteria are critically reviewed.
The attempts of various scientists to transform the liquid self-emulsifying
drug delivery systems (SEDDS) to solid-SEDDS by adsorption, spray
drying, lyophilization, melt granulation, extrusion, and so forth to
formulate various dosage forms like self emulsifying capsules, tablets,
controlled release pellets, beads, microspheres, nanoparticles,
suppositories, implants, and so forth have also been included.
Formulation of SEDDS is a potential strategy to deliver new drug
molecules with enhanced bioavailability mostly exhibiting poor aqueous
solubility. The self-emulsifying system offers various advantages over
other drug delivery systems having potential to solve various problems
associated with drugs of all the classes of biopharmaceutical
classification system(BCS).[8]
Pranay Wal et al., [2013] has described that Increasing numbers of
experimental investigations and recently also of clinical trials strongly
suggest an integral involvement of the endothelin (ET) system in the
pathophysiology of a variety of disease states, mainly of the
cardiovascular system. Ambrisentan (LU208075)approved by the US
Food and Drug Administration in 2007, a selective ETA-receptor
antagonist, is an orally active diphenylpropionic acid derivative that was
recently approved for treatment of pulmonary arterial hypertension (PAH)
in patients with World Health Organization class II or III symptoms.. It
has been shown to have a very promising efficacy to safety ratio in the
initial clinical trials. Phase II and Phase III trials with ambrisentan in
pulmonary arterial hypertension have been performed. Pulmonary
arterial hypertension (PAH) is a rare and progressive disease of the
pulmonary arterial circulation that is characterized by a progressive rise
in pulmonary vascular resistance, eventually leading to right-heart
failure and death. Endothelin (ET) is a potent vasoconstrictor with
mitogenic, hypertrophic and pro-inflammatory properties. Therefore,
2.LITERATURE REVIEW
Department of Pharmaceutics Page 35
blockade of ET receptors has been suggested as an attractive target in a
number of acute and chronic cardiovascular indications, including
pulmonary arterial hypertension (PAH), systemic hypertension, and heart
failure. In Phase III clinical trials in patients with PAH, ambrisentan (2.5–
10mg orally once-daily) improved exercise capacity, time to clinical
worsening, WHO functional class, and quality of life compared with
placebo. This review discusses the endothelin family of proteins and
receptors and their role in the pathophysiology of pulmonary
hypertensive diseases.
Sarfaraz et al., (2013) Immediate release tablets are highly accepted fast
growing drug delivery systems and thus, an attempt was made to
improve the onset of action of drug. To achieve this goal, selective
superdisintegrants croscarmellose sodium, crospovidone and sodium
starch glycolate in different concentrations (2.5 – 7.5%w/w), were
evaluated for their effect on the disintegration behaviour of tablets, while
microcrystalline cellulose and lactose were used as diluents. The tablets
were prepared by direct compression method and were evaluated for
various physicochemical properties, FTIR, in vitro disintegration and in
vitro drug release studies.[12]
Rajesh et al., (2012) The task of developing immediate release tablet is
accomplished by using suitable diluents and superdisintegrants. Faster
disintegration of the tablet administrated orally minimizes absorption
time and improves its bioavailability in less time. The formulation
development work was initiated with wet granulation method and a total
of 8 formulations (F1-F8) were made. The formulated tablets were
evaluated for various pre compression parameters and post compression
parameters like thickness, hardness, weight variation, friability,
disintegration test, drug content uniformity and in vitro release studies.
The formulation F8 showed satisfactory physical parameters, and it was
found to be stable among other formulations.
2.LITERATURE REVIEW
Department of Pharmaceutics Page 36
Natarajan R et al., (2011) to formulate various formulations of
immediate release tablet of Paroxetine using different superdisintegrants
(Sodium Starch Glycolate, Croscarmellose, Crospovidone) and different
grades of di calcium phosphate by wet granulation method. The drug-
excipients interaction was investigated by FTIR. The granules and tablets
of Paroxetine were evaluated for various pre and post compression
parameters like Angle of repose, Compressibility index, Hausner’s ratio,
Tablet hardness, Friability, Weight variation, Drug content and in vitro
dissolution. Their results were found satisfactory. The in vitro dissolution
studies show the release is in the following order of superdisintegrants:
Sodium Starch Glycolate>Croscarmellose>Crospovidone. These results
suggest that, as determined by f2 factor (similarity factor) and maximum
in vitro dissolution was found to be with Formulation F-7 and it clearly
shows due to Sodium Starch Glycolate (4%).[10]
Patel N. et al., (2011) Opadry White was used for coating the core
tablets. Total 16 batches were formulated. In that last 6 batches were
optimized by process parameters like kneading time, lubrication time
and by sizing. These formulations were evaluated for physical parameters
of tablet, drug-excipient compatibility study, and in- vitro drug release
study. The optimize formulation F8 release profile was match with
marketed formulation and release rate was maximum than other
batches. Stability study of the optimized formulation indicates no
significant differences in release profile and drug content after a period of
one to three month. Immediate release dosage form of API was
formulated using Cros carmellose Sodium as superdisintegrant. [11]
Sheen et al., (1995) studied the formulation of poorly water-soluble
drug in solid dispersion to improve bioavailability. The results concluded
that the bioavailability of poorly water-soluble drug was increased from
water-soluble carrier and was further improved by the addition of a
surfactant.
3. AIMS AND OBJECTIVE
Department of Pharmaceutics Page 37
3.1. AIM
The main aim of the work is to formulate immediate release
tablets of Ambrisentan 10 mg by a direct compression method and to
evaluate the prepared tablets against the marketed product,
Letairis®.(Ambrisentan tablets, 10 mg)
3. AIMS AND OBJECTIVE
Department of Pharmaceutics Page 38
3.2. OBJECTIVE
Challenges
➢ To develop a cost effective formulation with direct compression
method with commercialization aspect.
➢ Direct compression process and with limited excipients will be
cost effective.
➢ Low solubility of API.
➢ To develop a robust formulation free from defects in flow and
compression.
➢ Since the drug load on the formulation is less than 10%,
overcoming the challenge of blend uniformity and content
uniformity with limited manufacturing steps is a challenge.
➢ Attaining uniform stability results of the finished product after
being processed.
4. Plan of Work
Department of Pharmaceutics Page 39
4. PLAN OF WORK
❖ Literature survey.
❖ Procurement of drug, other excipients.
❖ Preformulation Studies[3]
▪ Solubility
▪ Drug and excipient compatibility studies
▪ Bulk density
▪ True density
▪ Melting point determination
▪ Carr’s index
▪ Hausner’s ratio
▪ Angle of repose
❖ Formulation development
❖ Evaluation Studies[3]
• Weight variation
• Hardness
• Friability
• Thickness
• Disintegration time
• Content uniformity
• Invitro Dissolution study
• Stability Studies
5. DISEASE PROFILE
Department of Pharmaceutics Page 40
5. DISEASE PROFILE- PULMONARY ATREIAL HYPERTENSION
5.1. INTRODUCTION:
Pulmonary aterial hypertension is a syndrome resulting from
decreased flow of blood in the pulmonary vascualte due to increased
pulmonary vascular resistance (PVR) and right heart failure13. The
Revised world health organization (WHO) Classification has divided
pulmonary hypertension into five types. The incidence of PAH is
15/million in the population.
Fig.No:5. Difference between Healthy and affected vessel
Pulmonary arterial hypertension is associated with increased
PVR resulting from loss of vascular luminal cross-section due to
vascular remodeling produced by excessive vasoconstriction plays a
significant role in approximately 20% of patients14. Pulmonary arterial
hypertension is a panvasculopathy predominantly affecting small
pulmonary arteries15. Pulmonary arterial hypertension is
characterized by a variety of arterial abnormalities including intimal
hyperplasia, medialhypertropy, adventitial proliferation and
thrombosis in situ. Right ventricle function is a major determinant of
functional capacity and prognosis in PAH(1) while RV hypertrophy and
dilation is initiated by increased after load, the adequacy of RVs
compensatory response is quite variable amongst individuals.
Plumonary arterial hypertension is characterized by endothelial
5. DISEASE PROFILE
Department of Pharmaceutics Page 41
dysfunction, a decreased ratio of apoptosis/proliferation in pulmonary
artery smooth muscle cell and thickened disordered adventitia in
which there is excessive activation of adventitial metalloprotease16.
Fig.No:6. Pulmonary vascular changes in PAH leading to RV strain
PAH is characterized by platelets that are depleted by serotonin and
elevation of plasma serotonin. In PAH, endothelial dysfunction is
characterized by increased production of vasoconstrictor/mitogenic
compounds such as endothelin and thromboxane and deficient
production of vasodilators like prostacycline, there is also increased
production of thromboxane A2 and deficient prostacyclin17 leading to
thrombosis, proliferation and vasoconstriction.
Fig.No:7. Difference between normal and affected vessel in lungs
Decreased level of endothelial nitric oxide has been observed in PAH
as it is quickly inactivated by PDE-5. Endothelian-1 is a
5. DISEASE PROFILE
Department of Pharmaceutics Page 42
vasoconstrictor and a smooth muscle mithogen that may contribute to
the development of PAH.
5.2.CLASSIFICATION OF PAH AS PER WHO:
• Pulmonary arterial hypertension
➢ Idiopathic PAH
➢ Familial PAH
➢ Associated with PAH
• Connective tissue disorder
• Congential systemicto pulmonary shunts
• Portal hypertension
• Human immunodeficiency virus infection
• Drugs and toxins
• Pulmonary hypertension with left heart disease
• Pulmonary hypertension associated with lung disease or
hypoxemia
• Pulmonary hypertension due to chronic thrombolic or embolic
disease
5.3.CAUSES :
• History of heart murmur
• Deep venous thrombosis (DVT) or pulmonary embolism (PE)
• Raynaud phenomenon
• Arthritis or arthralgias
• Rash
• Heavy alcohol consumption
• Hepatitis
• Heavy snoring
• Daytime hypersomnolence
• Morning headaches
• Morbid obesity
• Family history of pulmonary hypertension
• Drug use, in particularly diet drugs and illicit drugs
• Medications
5. DISEASE PROFILE
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5.4. SYMPTOMS:
Patients with PAH may also have nonspecific symptoms secondary to
pulmonary hypertension. These may include the following:
• Dyspnea upon exertion
• Fatigue
• Lethargy Dizziness or fainting spells (syncope)
• Syncope with exertion
• Chest pain
• Anorexia
• Right upper quadrant pain
• welling (edema) in your ankles, legs and eventually in your
abdomen (ascites)
• Bluish color to your lips and skin (cyanosis)
• Racing pulse or heart palpitations
Less common symptoms include the following:
• Cough
• Hemoptysis
• Hoarseness (due to compression of the recurrent laryngeal nerve
by the distended pulmonary artery)
5.5. PAH Diagnosis:
1. Blood tests: potential diseases that are associated with PAH
as well as other signals of PAH. These include an HIV test;
thyroid tests; autoimmune disease panels to test for systemic
lupus erythematosus and scleroderma; liver tests; as well as
standard tests like a complete blood count (CBC) and
chemistry tests. It may also include a test to measure a
hormone called brain natriuretic peptide (BNP) that helps
evaluate the amount of stress on the heart.
2. Chest X-ray: A chest X-ray gives a picture of heart, lung, and
chest to look for signs of pulmonary hypertension.
3. CT scan: A CT scan provides with a more detailed, visual
picture of lungs, blood vessels and heart.
5. DISEASE PROFILE
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4. Electrocardiogram: This noninvasive test shows the electrical
activity of the heart and can detect abnormal heart rhythms. It
is a useful test to identify different causes for symptoms
associated with PAH.
5. Pulmonary function tests: These simple breathing tests
measure how much air you can hold in your lungs and how
much air moves in and out of your lungs.
6. Exercise tolerance test (also known as the 6-minute walk
test): This test is used to compare exercise capacity, oxygen
levels and symptoms over time and to evaluate how these
characteristics change over time and with therapy.
7. Cardiopulmonary exercise testing (CPET or CPX): This test
measures how well heart and lungs are performing both at
rest and during exercise. CPET helps to understand the
amount of oxygen your body is using, the amount of carbon
dioxide body is producing, and the breathing pattern.
8. Ventilation-perfusion scan (VQ scan): This test examines air
and blood flow to the lungs and creates images use to look for
blood clots in the lungs.
9. Echocardiogram: This noninvasive test – a type of ultrasound
of the heart – looks at the chambers and valves of the heart,
determining their size and function. An echocardiogram will
detect some signs of PH in most patients with the disease,
making it very practical. While it does not directly measure
pulmonary arterial pressure (PAP), it does give an idea if PH is
present and how severe it is. Unfortunately, it cannot
guarantee the diagnosis of PH by itself, which means further
testing is likely.
10. Cardiac MRI (Magnetic Resonance Imaging): This is an MRI
test that evaluates the heart size and function more accurately
than the echocardiogram and gives a better picture of the
heart muscles, valves, and blood work. It may also show any
5. DISEASE PROFILE
Department of Pharmaceutics Page 45
congenital heart disease (an abnormality in the heart that
developed before birth).
11. Right-sided heart catheterization: will likely recommend a
right-sided heart catheterization because it is the clearest test
for showing which of the five forms of PH. This test involves
placing a small tube, known as a catheter, into a large vein in
the neck, arm, or groin. This catheter is then threaded
through the different chambers of the heart and lung to
measure the pressure in each. How much blood the heart
pumps each minute, known as cardiac output, is also
measured. The amount of resistance to blood flow in the
lungs, known as the pulmonary vascular resistance, can be
calculated from these measurements and are important
indicators of how severe PAH is.
5.6. TREATMENT:
A) MEDICATION:
1. Calcium Channel Blockers: Nifedipine, Diltiazem, Amlodipine
2. Vasodilators: Epoprostenol, Treprostinil, Iloprost
3. PAH, Prostacyclin Agonists: Selexipag
4. Endothelin-Receptor Antagonists : Bosentan, Ambrisentan,
Macitentan
5. Phosphodiesterase-5 Enzyme Inhibitors : Sildenafil,
Tadalafil, Vardenafil
6. Soluble Guanylate Cyclase (sGC) Stimulators: Riociguat
7. Cardiac Glycosides: Digoxin
8. Loop Diuretics : Furosemide, Bumetanide
9. Anticoagulants: Warfarin
10. Oxygen.
B) SURGERY:
• Atrial septostomy. If medications don't control pulmonary
hypertension, this open-heart surgery might be an option. In an
atrial septostomy, a surgeon will create an opening between the
5. DISEASE PROFILE
Department of Pharmaceutics Page 46
upper left and right chambers of heart (atria) to relieve the
pressure on the right side of heart. Atrial septostomy can have
serious complications, including heart rhythm abnormalities
(arrhythmias).
• Transplantation. In some cases, a lung or heart-lung transplant
might be an option, especially for younger people who have
idiopathic pulmonary arterial hypertension.
Major risks of any type of transplantation include rejection of the
transplanted organ and serious infection, and you must take
immunosuppressant drugs for life to help reduce the chance of
rejection.
6. DRUG PROFILE
Department of Pharmaceutics Page 47
6. DRUG PROFILE - AMBRISENTAN
Description:
Ambrisentan, is an orally active endothelin
receptor antagonist that is selective for the endothelin type-A (ETA)
receptor antagonist indicated for the treatment of pulmonary arterial
hypertension. As an endothelin receptor antagonist, Ambrisentan
prevents endogenous endothelin peptide from constricting the
muscles in blood vessels, allowing them to relax and permit a
reduction in blood pressure. It contains a single chiral center
determined to be the (S) configuration. Ambrisentan was approved by
the U.S. Food and Drug Administration (FDA) and European
Medicines Agency, and designated an orphan drug, for the treatment
of pulmonary hypertension.
Chemical Structure
CAS number
177036-94-1
IUPAC Name
(S)-4-({3-[2-(dimethylamino)ethyl]-1H-indol-5-yl}methyl)-1,3-
oxazolidin-2-one
Description
White to off- white powder
Drug class
Pulmonary Arterial Hypertension Agents
BSC Classification Class II
6. DRUG PROFILE
Department of Pharmaceutics Page 48
Water Solubility
Ambrisentan is practically insoluble in aqueous solutions at low
pH. Solubility increases at higher pH.
pKa 4
Molecular weight: 378.428 g/mol
Pharmacodynamics:
Ambrisentan is an orally active, non-sulfonamide, propanoic –
class, endothelin receptor antagonist (ERA) that is selective for
endothelin type A (ETA) receptor. ETA receptor antagonist inhibit
phospholipase C-mediated vasoconstriction and protein kinase C-
mediated cell proliferation, while preserving nitric oxide and
prostacyclin production, cyclic GMP- and cyclic AMP –mediated
vasodilation, and endothelin-1 (ET-1) clearance that is associated with
the endothelin type B (ETB) receptor. ERAs have proven therapeutic
benefit in treatment of PAH in humans.Ambrisentan has a high
affinity against myocardial native ETA receptor, with selectivity for the
ETA receptor of approximately 4000-fold relative to the ETB receptor.
It is indicated for treatment of idiopathic (‘primary’) pulmonary
arterial hypertension (IPAH) and pulmonary arterial hypertension
(PAH) associated with connective tissue disease in patients with WHO
functional class II or III symptoms.
Pharmacokinetics:
Absorption:
Ambrisentan was well absorbed following oral administration. It
also showed high absolute oral bioavailability, indicating that it
undergoes little or no first pass metabolism. Cmax occurring around
1.5 hours post dose under both fasted and fed condition. Cmax and
AUC increase dose proportionally over the therapeutic dose range.
6. DRUG PROFILE
Department of Pharmaceutics Page 49
Distribution:
Ambrisentan binds to plasma proteins to a higher extent
(98.9%) and specifically albumin was the primary binding protein.
Metabolism:
Ambrisentan is metabolized by phase I oxidative metabolism
and by phase II hepatic glucuronidation. About 30% of the
administered dose undergo oxidative metabolism mainly by CYP3A4
and to a lesser extent by CYP3A5 and CYP2C19. The identified
metabolites of ambrisentan includes
• 4,6 dimethyl-2-hydroxypryimidine(M1)
• Ambrisentan glucuronide (M2)
• Hydroxylated ambrisentan (M3)
• O-demethylated ambrisentan (M4)
• Dihydroxylated ambrisentan (M5)
• Dihydroxylated ambrisentan glucuronide (M6)
• Hydroxylated ambrisentan glucuronide (M7)
• O-demethylhydroxymethyl ambrisentan (M8)
Excretion:
The major route of elimination of elimination for ambrisentan
and its metabolites is biliary excretion in faeces (65.4%), with urinary
excretion (22.1%) representing minor route.
Drug indication:
Ambrisentan is indicated for the treatment of pulmonary arterial
hypertension (PAH) (WHO Group 1):
• To improve exercise ability and delay clinical worsening.
• In combination with tadalafil to reduce the risks of disease
progression and hospitalization for worsening PAH, and to
improve exercise ability.
6. DRUG PROFILE
Department of Pharmaceutics Page 50
Studies establishing effectiveness included predominantly
patients with WHO Functional Class II–III symptoms and etiologies of
idiopathic or heritable PAH (60%) or PAH associated with connective
tissue diseases (34%).
DOSAGE AND ADMINISTRATION:
Adult Dosage
Initiate treatment at 5 mg once daily, with or without tadalafil
20 mg once daily. At 4-week intervals, either the dose of Letairis or
tadalafil can be increased, as needed and tolerated, to Ambrisentan 10
mg or tadalafil 40 mg.
SIDE EFFECTS:
Clinically significant adverse drug reactions that appear
which includes,
• Embryo-fetal Toxicity
• Fluid Retention
• Pulmonary Edema with PVOD
• Decreased Sperm Count
• Hematologic Changes
Brand names
Letairis®(Ambrisentan tablets) 10 mg
Uses:
Ambrisentan is indicated for the treatment of pulmonary arterial
hypertension (WHO Group 1) in patients with WHO class II or III
symptoms to improve exercise capacity and delay clinical worsening.
7. EXCIPIENT PROFILE
Department of Pharmaceutics Page 51
7. EXCIPIENT PROFILE
7.1 CROSCARMELLOSE SODIUM[20]
Synonym :
Ac-Di-Sol;Crosslinkedcarboxymethylcellulose sodium; Modified
cellulose gum; Pharmacel XL; carmellosumnatricumconexum.
Description : White odorless or greyish white powder.
Structure :
IUPAC name: Acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium
Chemical name:
Croscarmllose; Sodium Carboxymethylcellulose; Carmellose
Molecular formula : C28H30Na8O27
Molecular Weight : 982.44 g/mol
Solubility:
Insoluble in water, although croscarmellos Sodium rapidly swells
to 4–8 times its original volume on contact with water. Practically
insoluble in acetone, ethanol and toluene.
Safety :
It is a nontoxic and nonirritant material. However, oral
consumption of large amounts of croscarmellose sodium may havea
laxative effect, although the quantities usedin solid dosage formulations
are unlikely to cause such problems.
Application
• Disintegrant for capsules, tablets, and granules
• Disintegrant in tablets : 0.5 – 5.0 %
7. EXCIPIENT PROFILE
Department of Pharmaceutics Page 52
• Disintegrant in capsules : 10 – 25 %
Stability and storage conditions:
• Croscarmellose sodium is a stable though hygroscopic material.
• Croscarmellose sodium should be stored in a well-closed container
in a cool, dry place.
7.2. LACTOSE MONOHYDRATE[20]
Synonym:
CapsuLac; GranuLac; Lactochem; lactosummonohydricum;
Monohydrate; Pharmatose; PrismaLac; SacheLac; SorboLac; SpheroLac;
Super Tab 30GR; Tablettose.
Description:
Lactose occurs as white to off-white crystalline particles or powder.
Lactose is odorless and slightly sweet-tasting; a-lactose is approximately
20% as sweet as sucrose, while b-lactose is 40% as sweet
Structure :
IUPAC name:
(2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6[(2R,3S,4R,5R)-4,5,6-
trihydroxy-2-(hydroxymethyl)oxan-3yl] oxyoxane-3,4,5-triol
Chemical name:
O-b-D-Galactopyranosyl-(1!4)-a-D-glucopyranose monohydrate
Molecular formula : C12H22O11H2O
Molecular Weight : 360.31
Solubility : Practically insoluble in chloroform, ethanol, ether.
7. EXCIPIENT PROFILE
Department of Pharmaceutics Page 53
Water
• 1 in 5.24
• 1 in 3.05 at 400C
• 1 in 2.30 at 500C
• 1 in 1.71 at 600C
• 1 in 0.96 at 800C
Melting point : 201–2020C
Applications :
Lyophilization aid, Tablet binder, Tablet and capsule diluent,
Tablet and capsule filler.
Storage :
Mold growth may occur under humid conditions (80% relative
humidity and above). Lactose may develop a brown coloration on storage,
the reaction being accelerated by warm, damp conditions; Lactose should
be stored in a well-closed container in a cool, dry place.
7.3. MICROCRYSTALLINE CELLULOSE[20]
Synonym :
Avicel PH; Cellulose gel; Crystallinecellulos; E460; Emcocel;
Fibrocel; Tabulose; Pharmacel.
Description :
Microcrystalline cellulose is a purified, partially depolymerized
cellulose that occurs as a white, odorless, tasteless, crystalline powder
composed of porous particles
7. EXCIPIENT PROFILE
Department of Pharmaceutics Page 54
Structure :
IUPAC name:
2-[4,5-dihydroxy-2-(hydroxymethyl)-6-methoxyoxan-3-yl]oxy-6-
(hydroxymethyl)-5-methoxyoxane-3,4-diol
Chemical name: Cellulose gel; Cellulose, microcrystalline
Molecular formula: C14H26O11
Molecular Weight :370.351 g/mol
Solubility :
Slightly soluble in 5% w/v sodium hydroxide solution; practically
insoluble in water, dilute acids, and most organic solvents
Melting point : Chars at 260–2708C.
Applications :
Adsorbent, Suspending agent, Tablet and capsule diluent, Tablet
disintegrant
Safety :
Microcrystalline cellulose is widely used in oral pharmaceutical
formulations and food products and is generally regarded as a relatively
nontoxic and nonirritant material.
7. EXCIPIENT PROFILE
Department of Pharmaceutics Page 55
Storage :
Microcrystalline cellulose is a stable though hygroscopic material.
The bulk material should be stored in a well-closed container in a cool,
dry place.
7.4. MAGNESIUM STEARATE[20]
Synonym :
Dibasic magnesium stearate; magnesium distearate; magnesia
stearas; magnesium octadecanoate; octadecanoic acid, magnesiumsalt;
stearic acid, magnesium salt; Synpro 90.
Description :
Magnesium stearate is a very fine, light white, precipitated or
milled, impalpable powder of low bulk density, having a faint odor of
stearic acid and a characteristic taste. The powder is greasy to the touch
and readily adheres to the skin.
Structure :
IUPAC name : Magnesium; octadecanoate
Chemical name :
Magnesium stearate; Magnesium octadecanoate; Magnesium
distearate; Synpro 90; Octadecanoic acid,
Molecular formula : C36H70MgO4
Molecular Weight : 591.24 g/mol
Solubility :
7. EXCIPIENT PROFILE
Department of Pharmaceutics Page 56
Practically insoluble in ethanol, ethanol (95%), ether and water;
slightly soluble in warm benzene and warm ethanol (95%).
Melting point : 117–1500C
Applications : Tablet and Capsule Lubricant
Safety :
It is generally regarded as being nontoxic following oral administration.
However, oral consumption of large quantities may produce a laxative
effect or mucosal irritation.
Storage:
Magnesium stearate is stable and should be stored in a well-closed
container in a cool, dry place.
8. MATERIALS AND EQUIPMENTS USED
Department of Pharmaceutics Page 57
8. MATERIALS AND EQUIPMENTS USED
8.1. Active pharmaceutical Ingredient
Table 2. Active Pharmaceutcal Ingredient and its manufacturer.
API Manufacturer
Ambrisentan Aurobindo Pharma
8.2. Excipients
Table 3. Excipients and its manufacturers.
Excipients Manufacturer
Lactose Monohydrate SPI Pharma
Microcrystalline cellulose PH101 Roquette Pharma
Croscarmellose sodium Avantor Performance Materials
Magnesium Stearate Firmenich Pharma
8.3.Equipments used:
➢ Analytical balance,
➢ Sieves,
➢ Proton mini press compression machine, 10 station,
➢ vernier calliper,
➢ Electrolab Friability tester,
➢ Hardness tester,
➢ Electrolab Tap Density Tester,
➢ Electrolab Disintegration Tester,
➢ Ohaus Moisture analyser,
➢ Funnel and stand for Angle of repose,
➢ UV spectrophotometry,
➢ Dissolution test apparatus,
➢ Water's HPLC
9. PREFORMULATION
Department of Pharmaceutics Page 58
9. PREFORMULATION
It is the first step in rational development of dosage forms of
drug substance. Preformulation testing is defined as investigation of
physical and chemical properties of a drug substance alone and when
combined with excipients. The overall objective of preformulation
testing is to generate information useful to the formulator in
developing stable and bio-available dosage forms that can be mass-
produced. Preformulation investigations are designed to identify those
physicochemical properties and excipients that may influence the
formulation design, method of manufacture and pharmacokinetic
biopharmaceutical properties of the resulting product.
Preformulation parameters
9.1.Organoleptic properties
This includes recording of appearance,colour, odour and taste of
the drug using descriptive terminology. Record of colour of early
batches is very useful in establishing appropriate specifications for
later production. Colour white.
9.2.Physicochemical characterization:
9.2.1.Density measurement:
Granules density may influence compressibility, tablet porosity,
dissolution and other properties. Different types of density calculation
were done to characterize the API and its flow property. Generally two
types of density are determined i.e., bulk density and tapped density.
The methods followed for calculation of the above two densities are
determined by the following ways.
9.2.2.Bulk density:
It is a measure used to describe the packing of particles or
granules. An accurately weighed quantity of powder, which was
previously passed through sieve #40 [USP] and carefully poured bed
was made uniform without disturbing. Then volume measure was
called as the bulk volume and the bulk density is calculated by
following formula.
9. PREFORMULATION
Department of Pharmaceutics Page 59
Bulk density= weight of powder / Bulk volume
9.2.3.Tapped density:
After measuring the bulk volume the same measuring cylinder
was set into tap density apparatus. The tap density apparatus was set
to300 taps drop per minute and operated for 500 taps. Volume was
noted as (Va)and again tapped for750 times and volume was noted as
(Vb). If the difference between Va and V b not greater than 2% then Vb is
considered as final tapped volume. The tapped density is calculated by
the following formula.
Tapped density= Weight of powder /Tapped volume
9.2.4.Flow properties:
The flow properties from a material result from many forces.
There are many types of forces hat can act between solid particles:
frictional forces, surface tension forces, mechanical forces caused by
interlocking of particles of irregular shapes, electrostatic forces and
cohesive or van der vaals forces. These forces can effect granule
properties such as particle size, particle size distribution, particle
shape, surface texture or roughness, residual surface energy and
surface area.
9.2.5.Compressibility index:
Pharmaceutical powders are broadly classified into free flowing
and cohesive. Powders are more often compressed into tablets using a
pressure of 5kg/cm2. This is called compression or compaction.
During this process the porosity of the powder changes. The
compression properties of most drugs are very poor. Therefore
compression vehicles such as lactose, calcium phosphate and
microcrystalline cellulose are included in tablet formulations.
Normally low dose drugs (<50mg) are prepared by direct compression.
Tablet materials should be plastic that is capable of undergoing
permanent deformation yet exhibit brittleness. Percentage
compressibility also known as Carr’s consolidation index is indirectly
9. PREFORMULATION
Department of Pharmaceutics Page 60
related to the relative flow rate, cohesiveness and particle size. It is a
simple, fast and popular method for predicting powder flow
characteristics.
Table 4. compressibility and flowability.
Percentage compressibility Flowability
5-10 Excellent
12-16 Good
18-21 Fair
23-25 Poor
Carr’s consolidation index= [(Tapped density-Fluff density)/tapped
density]*100
Compressibility index can be a measure of the potential
strength that a powder could build up in its arch in a hopper and also
the ease with which such an arch should be broken.
9.2.6.Angle of repose
The angle of Repose is defined as the maximum angle possible
between the surface of a pile of powder and the horizontal plane.
θ= Tan-1 (h/r)
Where
‘h’ = height of the pile
‘r’ = radius of the pile
Values of Ө are rarely less than 200, and values of up to 400
indicate reasonably flow potential. Above 500, however, the powder
flows only with great difficulty. In general, the angle of repose
increased with decreasing particle size. The addition of talk in low
concentration decreases the repose angle, but in higher concentration
it increases the angle.
9. PREFORMULATION
Department of Pharmaceutics Page 61
Table 5. Flow Properties and Corresponding Angles of Repose
Flow Property Angle of Repose (degree)
Excellent 25-30
Good 31-35
Fair – aid not needed 36-40
Passable - may hang up 41-45
Poor – must agitate, vibrate 46-55
Very poor 56-65
Very very poor >66
9.2.7.Hausner ratio
It is the ratio of bulk volume or tapped density to bulk density.
Hausner’s ratio is an important character to determine the flow
property of powder and granules. Thiscan be calculated by the
formula
Hausner ‘s ratio=Tapped density/Bulk density
Value < 1.25 indicate good flow (=20% carr’s index)
While > 1.50 indicate poor flow (-35% carr’s index)
Table 6. Flow property and corresponding Hausner’s ratio.
Flow Character Hausner’s Ratio
Excellent 1.2-1.3
Good 1.3-1.4
Fair 1.4-1.5
Poor 1.5-1.6
9.2.8.Particle size distribution
Particle size distribution is a very important in process
technique of final blend after blending. It is an important parameter to
determine the amount of fines as well as particle with larger particle
size in final blend. It also helps in keeping a check over uniformity of
distribution of blend over various sizes while carrying out consecutive
batches. Particle size determination was carried by arranging various
sieves of sizes #20, #40, #60, #80, #100, #140, #200 and Pan (for finer
9. PREFORMULATION
Department of Pharmaceutics Page 62
particles which passes even #200 sieve) in ascending order (i.e.,#20
sieve lies on top and pan at the bottom). Then the final blend of
accurately weighed quantity was placed on the top sieve. And the
sieves are placed in vibrosifter and allowed to run at 1.0 amplitude for
10 minutes. After the procedure difference of initial and final weight of
sieves were noted to calculate the percentage retention of the blend in
various sieves.
10. FORMULATION
Department of Pharmaceutics Page 63
10. FORMULATION
Batches and their composition:
Various batches were planned and executed with the unit
concentration of the ingredients used in the batch as shown in the
table below.
Table 7. Composition of unit dose of various trial batches.
S.No Ingredients F1 F2 F3 F4 F5 F6 F7
1 Ambrisentan 10 10 10 10 10 10 10
2 Lactose Monohydrate 98 91 84 77 70 63 56
3 Microcrystalline cellulose pH
101(MCC)
14 21 28 35 42 49 56
4 Croscarmellose sodium (CCS)
15 15 15 15 15 15 15
5 Magnesium stearate 3 3 3 3 3 3 3
Total 140 140 140 140 140 140 140
Procedure:
1. Weigh the API and excipients as per the above formula.
2. Sift the item #01, 02, 03 in #30 mesh.
3. Blend all the ingredients.
4. After blending the above mixture is prelubricated with
magnesium stearate.
5. Collect pooled sample blend for characterization.
6. Compress the final blend in a protn mini press rotary tablet
press with a target weight of 140 mg.
7. Collect the tablets, pick the tablets randomly and evaluated.
11. EVALUATION
Department of Pharmaceutics Page 64
11. EVALUATION.
11.1.Physical appearance
The physical appearance of a tablet, its visual identity and over
all “elegance” is essential for consumer acceptance. Included in this
category are tablet sizes, shape, colour, presence or absence of any
odour, taste, surface texture, physical flaws and consistency and
legibility of any identification marking.
11.2.Weight variation
Twenty tablets were selected randomly from the lot and weighed
individually to check for weight variation. Each tablet weight was then
compared with average weight variation. Each tablet weight was then
compared with average weight to ascertain the weight of the tablets
within the permissible limits. Not more than two of the individual
weights should deviate from the permissible limits. Not more than two
of the individual weights should deviate from the average weight by
more than 5% for >300mg tablets and none by more than double that
percentage.
Percentage deviation= [(Tablet weight- Average weight)/tablet
weight]*100
Table.8 USP Specification for uniformity of weight.
S.No Weight (mg) Maximum percentage
difference allowed
1. 130 or Less 10
2. 130 - 324 7.5
3. More than 324 5
11.3.Loss on drying
Loss on drying is an important parameter to determine the
moisture intake by blend during processing. Limit on loss on drying is
established from the sum of percentage moisture intake values of each
excipients used in the process. Percentage moisture in take was
determined during in process by using Ohaus Moisture Analyser. In
11. EVALUATION
Department of Pharmaceutics Page 65
which 1gm of blend was placed after taring the instrument at 105°C in
auto mode.
11.4.Friability
Friability test is performed to assess the effect of friction and
shocks, which may often cause the tablet to chip, cap or break. Roche
friabilator was used for the purpose. This device subjects number of
tablets to the combined effect of abrasion and shock by utilizing a
plastic chamber that revolves at 25 rpm dropping the tablets at a
distance of 6 inches with each revolution. Pre-weighed sample of
tablets were dusted and reweighed. Compressed tablets should not
lose more than 1% of their weight.
Percentage friability=[(w2-w1)/w1]*100
Where, W1= Weight of tablets before test; W2= Weight of tablets after
test
11.5.Thickness
The thickness was measured by using vernier calliper and
values were tabulated. Ten tablets of each batch were measured.
Average and standard deviation was calculated.
11.6.Hardness
The hardness of tablet is an indication of its strength.
Measuring the force required to break the tablet across tests it. The
force is measured in kg and the hardness of about 3-5 kg/cm2 is
considered to be satisfactory for uncoated tablets. Hardness of 10
tablets from each formulation is determined by Erweka hardness
tester.
11.7.Disintegration test
Breaking of tablets into smaller particles or granules is known
as disintegration and time taken for breaking of tablets in a suitable
medium is called disintegration time (DT). This test is not applicable
to modified-release tablets and tablets for use in the mouth. For those
tablets for which the dissolution test is included in the individual
monograph, the test for disintegration is not required. It is determined
by USP apparatus. It consists of 6 glass tube each 3 inches long, open
11. EVALUATION
Department of Pharmaceutics Page 66
at top and has 10 mesh screens at the bottom end of basket rack. One
tablet is placed in each tube and placed in a one litre beaker of water,
simulated gastric fluid or simulated intestinal fluid at 37 ± 2oC. It
moves up and down through a distances of 5 to 6 cm at 28 to 32 cpm.
Uncoated tablet has disintegration time as low as 5 minutes.
Majority of tablets has DT of 30 minutes. DT of enteric coated tablet is
one hour in simulated gastric fluid and two hours in simulated
intestinal fluid. DT for dispersible and soluble tablets is within 3
minutes.
11.8.Wetting time and water absorption ratio:
Wetting time of dosage form is related to with the contact angle.
Lower wetting time implies a quicker disintegration of the tablet.
Wetting time: It is closely related to the inner structure of the tablets and to
the hydrophilicity of the excipients. To measure wetting time, five
circular tissue papers of 10cm diameter are placed in a petridish with
a 10cm diameter. 10ml of water containing eosin, a water soluble dye,
is added to petridish. A tablet is carefully placed on the surface of the
tissue paper. The time required for water to reach upper surface of the
tablet is noted as a wetting time.
Water absorption ratio:
A piece of tissue paper folded twice was placed in a small Petri
dish containing 6 ml of water. A tablet was put on the paper & the
time required for complete wetting was measured. The wetted tablet
was then weighed. The water absorption ratio, R can be the
determined according to the following equation;
R = 100 (Wa-Wb) / Wb
Where,
Wb; The weight of the tablet before keeping in the petridish.
Wa; The wetted tablet from the petridish is taken and
reweighed.
11. EVALUATION
Department of Pharmaceutics Page 67
11.9. Analytical methods
Method of analysis for Dissolution
Dissolution Parameters
Table 9. Dissolution parameters
Apparautus USP Apparatus 2 (paddle)
RPM 75 RPM
Dissolution medium pH 5.0 Acetate buffer,
900ml
Time 5,10,15(Q),30 and 45 minutes
Sample collection volume 10 mL
Temperature 37.0±0.5°C
λ max 262 nm
Procedure
➢ Randomly select and weigh six tablets individually. Record the
weight of each tablet.
➢ Run the dissolution test on six tablets by applying the
parameters in the table.
➢ Withdraw sample solution portion of about 10 mL in each
dissolution vessel at the specified time point.
➢ Filter through a 0.45µ PVDF filter by discarding the first 4 mL of
the filtrate.
➢ Sample is analysed by using UV spectrophotometer.
11.10.STABILITY STUDIES:
➢ The optimized formulation is subjected to stability study as per
ICH guidelines to assess their stability with respect to their
physical appearance and release characteristics.
11. EVALUATION
Department of Pharmaceutics Page 68
11.11.Method of analysis for Assay
Chromatographic parameters
Table 10. Chromatographic parameters for Assay.
Mobile phase Buffer and acetonitrile (45:55)
Column X Bridge, C18, 150x4.6mm, 5.0µ Particle Size
Manufacturer: Waters, Part no:186003116
Flow rate 1.0mL/min
Sample
temperature
Ambient
Column
temperature
30°C
Wavelength 220nm
Injection volume 20µL
Run time 10 minutes
Sample retention
time
About 4.5 minutes
System
suitability
The RSD of Zolmitriptan peak area is NMT 2.0%
The USP tailing factor for ambrisentan peak is
NMT 2.0from standard preparation.
The USP plate count for ambrisentan peak , NLT
3000 from standard preparation.
Chromatographic procedure
➢ Perform an injection of diluent preparation.
➢ Perform five (5) replicate injections of the standard preparation.
➢ USP Tailing factor for Ambrisentan peak is NMT 2.0.
➢ The relative standard deviation (RSD) of the peak area is not
more than 2.0% for Ambrisentan in standard preparation.
➢ Perform an injection of test solution in duplicates.
➢ Record the chromatograms and calculate the percentage of
Ambrisentan dissolved as per the formula
11. EVALUATION
Department of Pharmaceutics Page 69
Percentage Assay
=𝐴𝑡
𝐴𝑠×𝑊𝑠
100×
5
50×𝑉1
𝑊𝑇×𝑉3
𝑉2×
𝑃
100×𝑇𝑊
𝐿𝐶× 100
Where,
At = Peak area of ambrisentan from the chromatogram of the assay
preparation.
As = Average peak area of ambrisentan from the chromatograms of
the standard solution.
Ws = Weight of Ambrisentan WRS taken in mg.
WT =Weight of blend sample taken in mg.
P = Potency of Ambrisentan WRS on as is basis.
LC = Label claim of Ambrisentan tablet, in mg.
V1 =Respective volume of the standard volumetric flask used for
sample stock preparation in ml.
V2 =Respective volume of sample pipetted in ml.
V3 =Respective volume of volumetric flask used for sample
preparation in mL.
11.12.Content Uniformity
=𝐴𝑡
𝐴𝑠×𝑊𝑠
100×
5
50×
𝑃
100×𝑉
𝐿𝐶× 100
Where,
At = Average peak area of Ambrisentan from the chromatograms of
the sample solution.
As = Average peak area of Ambrisentan from the chromatograms of
the standard solution
Ws = Weight of Ambrisentan WRS taken in mg.
P = Potency of Zolmitrptan WRS on as is basis.
LC = Label claim of Zolmitriptan tablet, in mg.
V =Respective volume of the standard volumetric flask used for
sample preparation in mL.
11. EVALUATION
Department of Pharmaceutics Page 70
11.13.Method of Analysis for Impurities and Degradants
Chromatographic parameters
Table 11. Chromatographic parameters for Impurities and
degradants.
Mobile phase Mobile phase A= Buffer
Mobile phase B= Acetonitrile
Column Sunfire C18,4.6 x 250 mm, 5.0 µm particle size
Gradient Time
Mobile phase
A (%)
Mobile phase
B (%)
0 50 50
5 50 50
15 32 68
20 25 75
25 25 75
30 50 50
40 50 50
Flow rate 1.0 mL/min
Sample temperature Ambient
Column temperature 35°C
Wavelength 220nm
Injection volume 10µL
Run time 40 minutes
Sample retention
time
About 12 minutes
Sample preparation Sample preparations containing Ambrisentan
about 1000 µg/mL.
System suitability The RSD of Ambrisentan peak area is NMT 5.0%
from standard solutions.
The theoretical plate count for Ambrisentan is
not less than 5000 from standard solution.
The tailing factor for Ambrisentan is not more
than 2.0 from standard solution
11. EVALUATION
Department of Pharmaceutics Page 71
Chromatographic procedure
➢ Perform an injection of diluent preparation.
➢ Perform five (6) replicate injections of the standard preparation.
➢ The relative standard deviation (RSD) of the peak area is not
more than 5.0% for Ambrisentan peak in standard preparation.
➢ The theoretical plate count for Ambrisentan should not be less
than 5000.
➢ The tailing factor for Ambrisentan should not be more than 2.0.
➢ Perform an injection of placebo solution.
➢ Perform an injection of test solution.
➢ Record the chromatograms and calculate the percentage of
impurities and degradants as per the formula.
Calculations
Percentage of known impurity:
=𝐴𝑇1
𝐴𝑆×𝑊𝑆
100×
5
100×50
𝑊𝑇×𝐴𝑊
𝐿𝐶×
𝑃
100× 𝑅𝐹 × 100
Percentage of Known impurity
=𝐴𝑇2
𝐴𝑆×𝑊𝑆
100×
5
100×50
𝑊𝑇×𝐴𝑊
𝐿𝐶×
𝑃
100× 100
Where,
At1 = Peak area of known impurity from the chromatogram of the
sample solution.
At2 = Peak area of unknown impurity from the chromatogram of the
sample solution.
As = Mean peak area of Ambrisentan from the chromatograms of
the standard solution.
Ws = Weight of Ambrisentan WRS taken in mg.
Wt = Weight of Ambrisentan tablets powder taken in mg.
Avg.wt= Average weight of tablets in mg.
P = Potency of Ambrisentan WRS on as is basis.
RF = Response Factor of the known impurity.
LC = Label claim of Ambrisentan tablet, in mg.
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 72
12. RESULT AND DISCUSSION
12.1.Pre formulation Studies:
API Characteristics
Bulk density : 0.291 g / mL
Tapped density : 0.641 g / mL
Compressibility index : 54.60
Hausner ratio : 2.20
PSD by Malvern master Sizer :
d10 : 6.7 microns
d50 : 31.4 microns
d90 : 143.3 microns
API Manufacturer : Zhezianghuahai pharmaceutical Co., Ltd
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 73
Table .No: 12. API Solubility
Water
0.1N HCL
Solubility
(mg/ml)
Solution Stability
(% degradation) Solubility
(mg/ml)
Solution Stability
(% degradation)
24hrs
48hrs
24hrs
48hrs
0.04670 0.0470
6 0.04661 0.03948 0.03664 0.03349
pH 3.0 Buffer
pH 4.5 Acetate buffer
Solubilit
y (mg/ml)
Solution Stability (% degradation)
Solubility (mg/ml)
Solution Stability (% degradation)
24hrs
48hrs
24hrs
48hrs
0.01812 0.01732 0.01626 0.10183 0.10182 0.10010
pH 5.0 Acetate buffer
pH 6.8 Phosphate buffer
Solubility
(mg/ml)
Solution Stability
(% degradation) Solubility
(mg/ml)
SolutionStability
(% degradation)
24hrs
48hrs 24hrs 48hrs
0.25395 0.25479 0.25204 3.98 4.00 3.97
pH 8.5 Borate buffer
Solubility
(mg/ml)
Solution Stability (% degradation)
24 hrs
48hrs
14.81 14.94 14.80
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 74
Based on the above results it is clear that Ambrisentan is less
soluble in acidic pH and the solubility increased with increase in pH.
12.2.RLD Characteristics
Letairis®(Ambrisentan tablets, 10 mg)
Lot# SBFW
Exp Date : 09/2018
Manufactured by : Gilead sciences, Inc. Foster City, CA
94404
Pack : Bottle containing 3 tablets stored in a
HDPE container with dunnage.
Average Tablet Weight : 148.8 mg
Average thickness : 3.28 mm
Average Hardness : 12 kP
Dissolution
Table 13. Percentage drug dissolved in RLD.
Time (minutes) Mean % Drug Dissolved
5 65
10 72
15 85
30 91
45 98
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 75
12.3.EVALUATION ON PRECOMPRESSION PARAMETERS:
Characteristics of final blend:
Final blend was characterized with various parameters like bulk
density, tapped density, angle of repose and loss on drying for each batch
and their results were tabulated below
Table 14. Result for bulk density, tapped density, angle of repose
and loss on drying for the trial batches.
Particulars F1 F2 F3 F4 F5 F6 F7
Bulk
density (g/mL)
0.56 0.60 0.54 0.56 0.60 0.58 0.61
Tapped
density (g/mL)
0.44 0.43 0.34 0.40 0.40 0.39 0.40
Angle of repose
Ø
36 39 37 32 33 32 33
% LOD 4.5 5.4 2.9 3.0 2.7 2.8 2.9
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 76
Particle Size Distribution
Particle Size Distribution for final blend of the trial batches were
performed and the results are tabulated below
Table 15. Particle size distribution results for the final blend of trial
batches.
Particulars F1 F2 F3 F4 F5 F6 F7
20 0 0 0 0 0 0 0
40 4 4 2 2 0 2 2
60 14 12 16 14 12 14 16
80 12 10 16 12 14 14 14
100 20 14 18 22 16 18 18
140 13 18 20 22 20 20 22
200 22 26 18 16 20 16 16
pan 15 16 10 12 18 16 12
Total 100 100 100 100 100 100 100
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 77
Blend Uniformity
Percentage content of samples from final blend of trial batches
were analyzed and the results are tabulated below
Table 16. Results of Blend uniformity samples of final blend of the
trial batches
S.No F6 F7 F8
1 96.7 97.6 98.9
2 100.6 98.7 99.5
3 96.7 97.4 99.9
4 99.8 99.6 99.6
5 99.6 98.9 99.8
6 99.3 99.6 99.1
7 98.1 100.2 98.1
8 100.9 100.1 99.6
9 97.9 100 100.8
10 98.7 99.1 101.2
AVG 98.8 99.1 99.65
Min 96.7 100.2 98.1
Max 100.9 97.4 101.2
%RSD 1.50 1.00 0.89
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 78
12.4.Tablet Characterization
Weight Variation:
Weight variation of all the batches were evaluated and the results
are tabulated below
Table 17. Results for weight variation of the trial batches
S. No F1 F2 F3 F4 F5 F6 F7
1 138.4 139.1 139.8 139,4 139.5 140.4 140.1
2 139.9 138.4 136.9 140.1 138.9 138.9 139.8
3 138.6 139.4 139.6 140.5 140.4 139.8 140.1
4 140.0 139.9 140.4 141.0 140.8 140.1 140.6
5 141.4 141.0 140.0 139.5 140.7 140.7 139.7
6 139.9 142.4 140.1 139.1 141.8 138.4 140.1
7 138.6 139.4 140.0 138.4 139.6 138.8 138.1
8 137.5 139.7 139.1 139.0 138.9 19.9 139.2
9 140.3 138.8 137.8 140.1 140.0 138.9 140.0
10 140.1 141.0 138.1 141.0 141.0 140.1 141.0
Avg 139.5 139.9 139.2 139.9 140.2 127.6 139.9
Min 137.5 138.4 136.9 138.4 138.9 19.9 138.1
Max 141.4 142.4 140.4 141.0 141.8 140.7 141.0
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 79
Thickness:
Thickness of ten tablets were evaluated from each batch and
tabulated in the table below
Table 18. Thickness of tablets of the trial batches.
S.No F1 F2 F3 F4 F5 F6 F7
1 3.16 3.16 3.15 3.17 3.15 3.15 3.16
2 3.18 3.17 3.16 3.16 3.16 3.16 3.15
3 3.17 3.16 3.14 3.15 3.16 3.17 3.15
4 3.14 3.16 3.14 3.16 3.15 3.16 3.15
5 3.16 3.18 3.13 3.14 3.15 3.15 3.16
6 3.16 3.16 3.14 3.14 3.18 3.16 3.17
7 3.19 3.17 3.14 3.16 3.15 3.17 3.16
8 3.17 3.18 3.15 3.15 3.15 3.16 3.18
9 3.18 3.17 3.12 3.15 3.12 3.14 3.16
10 3.16 3.18 3.15 3.14 3.15 3.14 3.14
Avg 3.17 3.17 3.14 3.15 3.15 3.16 3.16
Min 3.14 3.16 3.12 3.14 3.12 3.14 3.14
Max 3.19 3.18 3.16 3.17 3.18 3.17 3.18
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 80
Hardness:
Hardness for ten tablets for the trial batches were evaluated and
the observation was tabulated below.
Table 19.Hardness of ten tablets and its average for the trial
batches.
S.No RB-AMB-
001
RB-AMB-
002
RB-AMB-
003
RB-AMB-
004
RBSU-AMB-
005
RBSU-AMB-
006
RB-AMB-
007
1 10.00 10.50 10.10 9.81 10.10 11.10 9.20
2 10.10 10.60 10.80 9.80 10.50 10.30 10.00
3 10.20 10.40 10.90 10.00 10.40 10.50 9.80
4 10.00 10.10 10,3 11.00 10.30 10.20 9.60
5 9.60 10.20 9.20 11.20 10.20 9.80 10.00
6 10.10 9.90 10.40 10.70 10.90 10.20 9.40
7 9.90 9.70 9.60 10.90 11.10 10.40 10.40
8 10.40 9.90 9.10 11.00 10.10 10.60 10.20
9 9.60 10.00 9.20 9.90 9.70 10.90 10.80
10 10.80 10.10 9.00 10.40 9.20 10.10 10.90
Avg 10.07 10.14 9.81 10.47 10.25 10.41 10.03
Min 9.60 9.70 9.00 9.80 9.20 9.80 9.20
Max 10.80 10.60 10.90 11.20 11.10 11.10 10.90
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 81
Content Uniformity:
Ten tablets from each batch were analysed for content uniformity
and the results are tabulated below.
Table 20.Results of percentage content and %RSD of tablets of trial
batches.
S. No F1 F2 F3 F4 F5 F6 F7
1 99.9 96.7 97.9 99.9 99.7 100.3 99.1
2 92.0 97.9 98.9 100.4 100.0 100.5 101.9
3 97.4 99.0 99.8 101.3 100.6 100.2 100.9
4 94.9 101.0 101.7 101.7 100.4 98.9 99.2
5 95.8 103.1 101.1 101.3 99.2 99.4 99.5
6 96.4 104.9 99,4 101.1 100.8 100.4 100.7
7 99.2 100.4 99.2 99.9 100.2 100.9 99.8
8 99.1 100.2 100.6 99.8 100.4 99.6 100.6
9 103.2 99.9 100.4 101.3 100.2 100.4 99.8
10 105.1 99.2 100.1 102.9 100.0 99.9 100.9
AVG 98.3 100.2 100.0 101.0 100.2 100.1 100.2
Min 92.0 96.7 97.9 99.8 99.2 98.9 99.1
Max 105.1 104.9 101.7 102.9 100.8 100.9 101.9
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 82
Friability:
Initial weight, final weight and percentage weight loss of tablets
from each batch for checking whether they pass the test for friability.
And the results are tabulated below.
Table 21.Friability and its parameters for all the batches.
Parameters F1 F2 F3 F4 F5 F6 F7
Initial Weight (gm)
6.8412 6.7351 6.7638 6.9967 6.8011 6.6509 6.6789
Final Weight (gm)
6.8240 6.7102 6.7449 6.9716 6.7801 6.6499 6.6678
Percentage Weight loss
(%)
0.41 0.37 0.28 0.36 0.31 0.01 0.17
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 83
Disintegration Time:
Minimum and maximum time taken by the six tablets from each
batch was noted and tabulated in the table below
Table 22.Disintegration time of each batch.
Parameters RB-
AMB-001
RB-
AMB-002
RB-
AMB-003
RB-
AMB-004
RBSU-
AMB-005
RBSU-
AMB-006
RB-
AMB-007
Minimum
Time (sec) 30 32 1.01 40 42 44 35
Maximum
Time (sec) 45 47 1.25 55 53 49 45
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 84
12.5.Assay & Water by Kf
Results of assay and moisture content evaluated by karlfischer
reagent was tabulated below
Table 23. Assay and water by kf results of the trial batches
Parameters F1 F2 F3 F4 F5 F6 F7
Assay(%) 96.70 96.80 98.7 97.9 99.2 100.4 100.2
Water by Kf
(%)
5.22 5.01 4.97 4.96 4.82 4.68 4.49
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 85
12.6.Related substance
The analytical method for related substance was performed and
the highest unknown impurity and total impurity values of the respective
batches were tabulated below.
Table 24. Highest unknown impurity and total impurities results of
the respective batches.
Parameters F1 F2 F3 F4 F5 F6 F7
Highest Unknown Impurity
(%) 0.12 0.17 0.13 0.12 0.13 0.14 0.17
Total Impurities (%) 1.70 1.72 1.07 1.08 1.06 1.10 1.11
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 86
12.7.Dissolution[23]
Percentage release of drug was analyzed during 15 minutes of
dissolution and the results for the respective batches were tabulated
below.
Table 25.results of dissolution data of the trial batches.
Dissolution Media: 0.05 M Acetate Buffer, pH 5.0. USP type II (Paddle)
Spec: NLT 80%(Q) in 30 minutes
Particulars 5 10 15 30 45
RLD (Letairis) 65.93 72.08 85.45 91.32 98.21
F1 47.21 54.23 59.15 65.89 72.17
F2 51.33 57.74 61.26 67.21 75.32
F3 56.04 61.81 69.07 72.11 79.14
F4 62.62 68.39 72.22 76.64 81.66
F5 69.45 75.17 81.43 88.17 94.21
F6 74.92 79.38 84.64 90.31 99.74
F7 79.22 85.71 91.78 98.36 99.22
And the graphical representation of the batches is shown below.
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 87
Fig 8: Graphical representation of Percentage dissolution of the
batches F1-F4
Fig 9: Graphical representation of Percentage dissolution of the
batches F5-F7
0
20
40
60
80
100
120
0 10 20 30 40 50
Cu
mu
lati
ve %
Dru
g R
ele
ase
Time (mins)RLD (Letairis) F1 F2 F3 F4
0
20
40
60
80
100
120
0 10 20 30 40 50
Cu
mu
lati
ve %
Dru
g R
ele
ase
Time (mins)
RLD (Letairis) F5 F6 F7
12. RESULT AND DISCUSSION
Department of Pharmaceutics Page 88
12.8.Accelerated stability studies[21][22]
30 Tablets with 6g/yard of nylon coil as dunnage is packed in 75cc
Heavy Weight HDPE Bottle capped with 33mm Child resistant closure
having induction seal liner is loaded along with placebo for analytical use
in each condition.
Particulars Assay Dissolution Impurity
- D
Any
unknown
impurity
Total
impurity
Specification 90-110
NMT 80%
(Q) in 30
minutes
NMT
0.5%
NMT
0.2% NMT1.0%
F7
(ACC - 1M) 100.8 98 0.02 0.01 0.06
F7
(ACC - 2M) 99.5 97 0.02 0.01 0.05
F7
(ACC - 3M) 100.2 97 0.03 0.01 0.06
13. SUMMARY AND CONCLUSION
Department of Pharmaceutics Page 89
13. SUMMARY AND CONCLUSION
The present study involves formulation and evaluation of
immediate release tablets of Ambrisentan. Endeavours with respect to
Direct compression method used for formulating tablets was best
suitable to achieve 100% results.
Preformulation studies involving organoleptic bulk density,
angle of repose, tapped density, compressibility index, hausner ratio,
melting point range, pH and solubility were carried out as per USP
specifications.
Polymers such as Lactose Monohydrate, Microcrystalline
cellulose pH 101(MCC), Croscarmellose sodium (CCS) were utilized in
all the trails. All the physical evaluations carried in preformulation
studies were carried out on all the three different polymers utilized.
All the formulations exhibited values within the acceptable range.
Tablets were evaluated for weight variations, hardness,
friability, thickness and Dissolution studies.
Release studies were carried out in pH 5.0 Acetate buffer, for 45
minutes. Evaluated samples for all the Three polymer systems.
Results indicated that formulation F7, gave 98.36% release within 30
minutes. Assay was carried out for formulation F7 and was found to
be 100.2%.
Remaining formulations gave fluctuating release profiles. The
formulation F7 was considered to be better among the trails
accomplished.
14. BIBLIOGRAPHY
Department of Pharmaceutics Page 90
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